Common Pitfalls in the Evaluation

and Management of Headache

Case-Based Learning
Common Pitfalls in the
Evaluation and Management
of Headache
Case-Based Learning
Elizabeth W. Loder
The John R. Graham Headache Center, Brigham and Women’s Faulkner Hospital; and
Department of Neurology, Harvard Medical School, Boston, MA, USA

Rebecca C. Burch
The John R. Graham Headache Center, Brigham and Women’s Faulkner Hospital; and
Department of Neurology, Harvard Medical School, Boston, MA, USA

Paul B. Rizzoli
The John R. Graham Headache Center, Brigham and Women’s Faulkner Hospital; and
Department of Neurology, Harvard Medical School, Boston, MA, USA
University Printing House, Cambridge CB2 8BS, United Kingdom

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c Elizabeth W. Loder, Rebecca C. Burch, and Paul B. Rizzoli 2014



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Library of Congress Cataloging in Publication data
Loder, Elizabeth, author.
Common pitfalls in the evaluation and management of headache :
case-based learning / Elizabeth W. Loder, Rebecca C. Burch, Paul B.
Rizzoli.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-1-107-63610-1 (pbk.)
I. Burch, Rebecca C., author. II. Rizzoli, Paul, author. III. Title.
[DNLM: 1. Headache – diagnosis – Case Reports. 2. Headache –
therapy – Case Reports. WL 342]
RC392
616.8 491 – dc23 2013049904
ISBN 978-1-107-63610-1 Paperback
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................................................................
Every effort has been made in preparing this book to provide
accurate and up-to-date information which is in accord with accepted
standards and practice at the time of publication. Although case
histories are drawn from actual cases, every effort has been made to
disguise the identities of the individuals involved. Nevertheless, the
authors, editors, and publishers can make no warranties that the
information contained herein is totally free from error, not least
because clinical standards are constantly changing through research
and regulation. The authors, editors, and publishers therefore
disclaim all liability for direct or consequential damages resulting
from the use of material contained in this book. Readers are strongly
advised to pay careful attention to information provided by the
manufacturer of any drugs or equipment that they plan to use.
We dedicate this book to the memory of Dr. John Ruskin Graham, an
early pioneer in the field of headache medicine and founder of our
Headache Center at the Brigham and Women’s Faulkner Hospital in
Boston. His work and ideals live on at the Graham Headache Center.
We strive to uphold Dr. Graham’s legacy of kindness, understanding,
and expert care for those affected by headache disorders.
Contents
Preface page ix
Acknowledgements x

1 Confusing one benign headache with 8 Pitfalls in drug therapy to prevent

another 1 headaches 119
2 Mistaking primary headache for 9 Pitfalls in nonpharmacologic treatment
another condition 20 of headache 145
3 Missing dangerous causes of headache 38 10 Challenges and special situations in
headache management 162
4 Pitfalls in diagnostic testing: imaging
and lumbar puncture 54 11 Medicolegal pitfalls in headache
management 175
5 Pitfalls in diagnostic testing: blood,
urine, and other tests 73
6 When historical or examination findings
are missed or misinterpreted 84 Index 186
7 Errors in management of acute
headache 100

vii
Preface
The Illustrated Oxford Dictionary defines a pitfall as
“an unsuspected snare, danger, or drawback.” This idea
of dangers that are disguised or difficult to recog-
nize is reflected in the word’s second meaning, which
is a “trap or snare,” often a covered pit, into which
unwary animals (or doctors?) might fall. Most doc-
tors correctly realize that evaluation and treatment of
headaches can be challenging. They know that most
headaches are benign but fear missing the occasional
serious cause of headache. Some believe that headache
treatment is often unsuccessful and unrewarding.
To the extent that this aversion to headache
exists, we think it is unfortunate. In our experience,
headache diagnosis is mostly straightforward. Further-
more, headache medicine is often fascinating and grat-
ifying. There are many unusual, intriguing types of
headache as well as new and highly effective treat-
ments for headache. We find that even “old-fashioned”
treatments, correctly applied, can produce satisfying
improvements for the right patient. As with any medi-
cal discipline, though, there are challenging aspects of
headache medicine. Our purpose in writing this book
is to make readers aware of the common and less obvi-
ous mistakes or pitfalls that we have encountered dur-
ing our years in practice – as well as those we have
observed in the practices of others.
There are many case-based neurology books avail-
able to practitioners who are interested in head pain,
including several with an exclusive focus on headache.
This book differs from those in two ways. First, the
cases in this book focus solely on challenging rather
than routine aspects of headache diagnosis and treat-
ment. Second, this book was written while the Inter-
national Classification of Headache Disorders (ICHD)
was being updated for just the third time since it was
issued in 1988. As a result, all of the information in
this book is current with the just-released ICHD-3 beta
version of the classification. The ICHD-3 beta is avail-
able free of charge at the website of the International
Headache Society (http://www.ihs-headache.org); you
may wish to print it for easy reference while reading
this book. We have not reproduced the diagnostic cri-
teria verbatim but have instead summarized the clini-
cal characteristics of each disorder, as specified in the
latest version of the classification.
Among us, the three authors of this book have a
combined experience of full-time Headache Medicine
practice of almost half a century. PR and EL are sea-
soned veterans and bring many years of clinical expe-
rience to bear. In contrast, RB is in the early phase
of her career; she has helped us focus on pitfalls and
mistakes to which newcomers or non-headache spe-
cialists might be prone. We hope these dual perspec-
tives make this a book that is useful to anyone who
might see headache patients, from family practition-
ers to pain specialists. After all, who among us has so
much experience that s/he cannot learn from the mis-
takes and near misses of others?
ix
 Acknowledgements
We offer our sincere thanks to Dr. Martin Samuels,
the legendary and beloved chairman of the Depart-
ment of Neurology at the Brigham and Women’s and
Brigham and Women’s Faulkner Hospitals in Boston.
His vision and backing led to the formation of the Divi-
sion of Headache within the Brigham Department of
Neurology – one of the first such divisions to be cre-
ated within the Neurology Department of a leading US
academic medical center. The Graham Headache Cen-
ter, and by extension this book, would not exist without
him.
We also thank Nicholas Dunton, our editor at
Cambridge University Press, for inviting us to write
x
this book. He tolerated with good humor the delay
caused by the tardy release of the third version of
the International Classification of Headache Disor-
ders. We hope he feels the result was worth the wait!
Our thanks also go to Kirsten Bot, assistant editor and
publishing assistant, who was so helpful with the final
phases of the book’s production. We also thank our
copy-editor, Anne Kenton, for her keen eye and atten-
tion to detail.
Elizabeth Loder, Rebecca Burch, Paul Rizzoli
July 2013
 Chapter
Confusing one benign headache

1 with another

Sometimes there is simply no mistaking which pri- Migraine or tension-type headache?

mary headache disorder is causing a patient’s prob-
lem. In these lucky instances, a patient spontaneously
provides a history so characteristic of a disorder that
there can be no doubt about the diagnosis. In specialty
headache practice, however, the patient who gives the
doctor such a “silver platter” description of a headache
problem is the exception and not the rule. Since the
primary, nondangerous headache disorders are clini-
cal diagnoses with, by definition, normal imaging and
laboratory findings, the patient history is critical to
making a diagnosis.
Unfortunately, as seasoned doctors know all too
well, obtaining an accurate history can be difficult.
This is particularly true for subjective symptoms such
as headache, where patients are struggling to describe
things like pain that cannot be directly observed or
measured by the doctor. Then too, patients also are
reporting symptoms that may come and go. Studies
show that patient recall of headache frequency and
features is low and deteriorates rapidly over time. A
missed or delayed diagnosis of a primary headache dis-
order is unlikely to expose patients to life-threatening
harm, but it does have consequences. For one thing,
it may mean the patient does not have the benefit of
new, highly effective treatments that work for some
headache problems and not others.
In this chapter we deal with cases in which a patient
with one of the “big three” common, nondangerous
primary headaches – migraine, tension-type, or clus-
ter headache – presented with ambiguous, overlapping
features and was therefore mistakenly diagnosed. To
minimize the chance of confusing these headaches,
it is worth becoming familiar with the many ways in
which the diagnostic features of common, nondanger-
ous headaches can overlap or be missed. Far and away
the most common pitfall is confusion about whether a
patient has migraine or tension-type headache, so we’ll
start there.
Case
A 34-year-old teacher was referred for consultation
regarding recurrent headaches for the last five years.
She was in good health and taking only occasional
ibuprofen to treat the headaches. She estimated that
headaches occurred on average twice a month, lasting
a day or two at a time, and had not recently changed
in character. They were bilateral, over her forehead,
and sometimes accompanied by neck pain. She said
that her job was stressful and wondered whether that
might be causing the headaches. She missed a day of
work every other month because of headaches, and
reported she was seeking treatment because her missed
work time had recently become “an issue” with her
employer. Physical and neurologic examinations were
normal except for mild tenderness on palpation over
the posterior neck and upper trapezius muscles. She
had previously been told that she probably had “ten-
sion headaches” and had been referred for physical
therapy but did not find that treatment effective.
How can migraine be reliably distinguished
from tension-type headache in this patient?
Careful evaluation of a full headache history is, in our
experience, the most useful method of distinguishing
between migraine and tension-type headache. In this
case, the patient did not spontaneously report char-
acteristic features of migraine such as nausea, vomit-
ing, photo or phonophobia, or worsening with physi-
cal activity. On the other hand, we did not ask!
Table 1.1 lists migraine features that are contained
in the diagnostic criteria for the disorder, along with
examples of how these features can be missed or misin-
terpreted. The diagnostic criteria for migraine have not
changed in the latest version (3-beta) of the Interna-
tional Classification of Headache Disorders (ICHD).

1
 Chapter 1: Confusing one benign headache with another

Table 1.1. Diagnostic features of migraine without aura: common pitfalls

“Silver platter” migraine
features
Duration of 4–72 hours
Unilateral (often over the
temple)*
Throbbing*
Moderate to severe pain
intensity*
Aggravated by or causing
avoidance of physical activity*
Nausea and/or vomiting#
Photophobia and
phonophobia#
* Only two of these four features are required for a diagnosis of migraine.
# Only one of these two features is required for a diagnosis of migraine. At least five attacks meeting criteria are required before migraine
without aura can be diagnosed.
“Not so obvious” migraine history
Duration uncertain because patient treats early or falls asleep. Shorter headaches often seen in children
Bilateral, posterior location of pain or prominent complaints of neck pain often lead to a diagnosis of
tension-type headache, but neck pain occurs in almost three-quarters of migraine attacks
Not all patients who otherwise have clear-cut migraine report throbbing pain; for many patients the
throbbing quality of the pain is obvious only in fully developed, longer duration headaches, so patients
who treat early or fall asleep may not experience this. Be alert for synonymous descriptions such as
“pounding” or “with my heartbeat”
In migraine attacks that are treated or do not progress, pain may never reach severe intensity.
Differences in pain reporting behaviors and pain perception among patients may affect patient ratings
of pain intensity
Sedentary patients may not have noticed this feature of their headaches
Vomiting is prominent in children with migraine, but often lessens as patients get older or headache
frequency increases. Decreased appetite may be present instead
Sensitivity to light or sound may become apparent only in headaches that have a chance to develop
fully; these symptoms may not develop in milder “forme fruste” or treated attacks

Some diagnostic criteria for migraine are more use-
ful than others when trying to decide between diag-
noses of migraine and tension-type headache. A sys-
tematic review of diagnostic studies showed that the
features most predictive of migraine as opposed to
tension-type headache were nausea, photo and phono-
phobia. When present, a typical history consistent with
migraine aura was, unsurprisingly, also highly predic-
tive of a migraine diagnosis.
What benign headache disorder might
account for this patient’s headaches?
Taking the limited history at face value, this patient’s
presentation is compatible with a diagnosis of tension-
type headache. It is tempting to think that the bilat-
eral, posterior location of the headache and associated
muscle tenderness clinch the matter. Migraine is, how-
ever, also in the differential. In fact, while tension-type
headache is the most common type of headache in the
general population, it is not the most common type
of headache in patients whose headaches are trouble-
some enough to seek medical care. A wealth of good
quality evidence suggests that once dangerous causes
of headache have been ruled out, the likelihood is
that patients consulting general physicians for trouble-
some headaches have migraine and not tension-type
headache. This is true even in patients like the one
in our case who present with features such as muscle
tension and neck pain and attribute their headaches
to stress. Muscle tension and neck pain are common
in both migraine and tension-type headache, as is
aggravation of headaches by emotional stress or ten-
sion. In fact, migraine patients who have these over-
lap characteristics (particularly neck pain) are most
likely to receive an incorrect diagnosis of tension-type
headache.
In this case, further questioning revealed that
the patient did have some loss of appetite with her
headaches and she became mildly sensitive to light,
features which support a diagnosis of migraine instead
of tension-type headache.
Discussion
Research in primary care settings shows that most
patients who seek care for troublesome headaches
receive a diagnosis of tension-type headache. This is
particularly likely to occur when patients report fea-
tures that are assumed to be highly characteristic of
tension-type headache – as the patient in our case
did. For example, many physicians (and patients, too)
assume that muscle pain or tenderness in the neck or
shoulders is synonymous with tension-type headache.
They may also assume the same thing in patients who

2
 Chapter 1: Confusing one benign headache with another

Table 1.2. Headache features and diagnosis of migraine

Specificity of
diagnosis for
Sensitivity of migraine vs. Likelihood ratio for diagnosis of
diagnosis of tension-type migraine (95% confidence
migraine (% of headache (% of interval)
Clinical feature patients) patients) Positive Negative
Nausea 82 96 23.2 (17.7–30.4) 0.19 (0.18–0.20)
Photophobia 79 87 6.0 (5.2–6.8) 0.24 (0.23–0.26)
Phonophobia 67 87 5.2 (4.5–5.9) 0.38 (0.36–0.40)
Exacerbation by physical activity 81 78 3.7 (3.4–4.0) 0.24 (0.23–0.26)
Unilateral 66 78 3.1 (2.8–3.3) 0.43 (0.41–0.45)
Throbbing or pulsating 76 77 3.3 (3.1–3.6) 0.32 (0.30–0.33)
Duration 4–24 hours 57 67 1.7 (1.5–2.0) 0.64 (0.58–0.71)
Duration 24–72 hours 13 91 1.4 (1.0–2.0) 0.96 (0.92–1.0)
Duration less than 4 hours 26 51 0.52 (0.44–0.61) 1.5 (1.3–1.6)

report high levels of psychologic or emotional tension.
Faced with a clinical situation like the one described
above, many physicians might consider sending the
patient for physical therapy or prescribing a muscle
relaxant, both treatments for tension-type headache.
The assumption that these symptoms are indica-
tive of tension-type headache probably stems from
the fact that the term “tension-type headache” sug-
gests that “tension” of some sort – perhaps psychologic
or muscle – may be the cause of headache. This is a
diagnostic pitfall, however, since evidence to support
these views is lacking. Although patients with tension-
type headache do, as a group, have more pericranial
tenderness than patients with migraine, muscle pain,
especially neck pain, is nonetheless very common in
migraine patients.
Electromyography (EMG) is not useful in distin-
guishing between the two disorders. Over a third of
migraine patients report neck pain with at least some
of their attacks. The neck pain can come before, dur-
ing, or even after attacks; this variability in its time
course makes it unlikely that neck pain is the “cause” of
headache. Both migraine and tension-type headache
patients have lower thresholds for experiencing pain
with pressure on muscles than do people without
headache; interestingly, the upper trapezius is the most
common site of tenderness.
Similarly, elevated levels of psychologic and emo-
tional distress are common in patients who seek med-
ical care for stubborn headaches, and may in part
reflect the impact of poorly controlled headaches on
their lives, rather than the other way around. It is
certainly the case, however, that emotional stress is a
commonly mentioned “trigger” of headache in both
tension-type and migraine patients. In fact, as demon-
strated in Table 1.2, there is considerable overlap of
commonly reported triggers between migraine and
tension-type headache. This underscores the surpris-
ingly low diagnostic value of many triggers and other
historical features commonly thought to be pathog-
nomonic of one or the other disorder. Having patients
keep a headache diary, such as the one illustrated
in Table 1.3, should help in distinguishing between
tension-type and migraine headaches when the diag-
nosis is uncertain.
In a large multinational study, over a thousand
patients consulting physicians with a complaint of
headache were asked to keep careful diaries of their
headaches for up to six months. These records were
then reviewed by headache experts, and the final
diagnosis of headache type was compared with the
diagnosis the treating physician had made at the
patient’s first visit. When physicians made a diagno-
sis of migraine, this diagnosis was correct in 98% of
patients. When physicians diagnosed non-migraine
headaches, such as tension-type headache, the diag-
nosis ultimately turned out to be wrong in 82% of
patients. The predominant reason for misdiagnosis
was having missed migraine. The authors of this study
concluded that “These findings support the diagnostic
approach of considering episodic, disabling primary
headaches with an otherwise normal physical exam

3
 Chapter 1: Confusing one benign headache with another

Table 1.3. A headache diary that can help distinguish between migraine and tension-type headache
Date Date Date Date Date
Just before the Yes Yes Yes Yes Yes
headache began, OR OR OR OR OR
was there any No No No No No
disturbance of
vision?
Just before the Yes Yes Yes Yes Yes
headache began, OR OR OR OR OR
did you have any No No No No No
weakness,
numbness, or
speech problems?
What did the pain Pounding, throbbing Pounding, throbbing Pounding, throbbing Pounding, throbbing Pounding, throbbing
feel like? OR OR OR OR OR
Steady, tightening, Steady, tightening, Steady, tightening, Steady, tightening, Steady, tightening,
squeezing squeezing squeezing squeezing squeezing
Where was the Right side of the Right side of the Right side of the Right side of the Right side of the
headache located? head head head head head
Left side of the head Left side of the head Left side of the head Left side of the head Left side of the head
Both sides of the Both sides of the Both sides of the Both sides of the Both sides of the
head head head head head
Did you experience Nausea Nausea Nausea Nausea Nausea
nausea or vomiting OR OR OR OR OR
with the Vomiting Vomiting Vomiting Vomiting Vomiting
headache? OR OR OR OR OR
Both Both Both Both Both
Did the headache get Yes Yes Yes Yes Yes
worse with OR OR OR OR OR
physical activity or No No No No No
keep you from
being active?
During the headache, Yes Yes Yes Yes Yes
were you bothered OR OR OR OR OR
by light? No No No No No
During the headache, Yes Yes Yes Yes Yes
were you bothered OR OR OR OR OR
by sound? No No No No No
At its worst, was your Mild Mild Mild Mild Mild
headache pain OR OR OR OR OR
mild, moderate, or Moderate Moderate Moderate Moderate Moderate
severe? OR OR OR OR OR
Severe Severe Severe Severe Severe
How long did your Less than 4 hours Less than 4 hours Less than 4 hours Less than 4 hours Less than 4 hours
headache last? OR OR OR OR OR
4–72 hours 4–72 hours 4–72 hours 4–72 hours 4–72 hours
OR OR OR OR OR
Longer than 72 Longer than 72 Longer than 72 Longer than 72 Longer than 72
hours or constant hours or constant hours or constant hours or constant hours or constant

to be migraine in the absence of contradictory
evidence.”
In summary, once a diagnosis of a primary
headache disorder has been made, it is appropriate
for physicians to think migraine. Prospectively kept
headache diaries are invaluable in making the diag-
nosis, as is a careful and probing history. Physicians
should avoid placing too much emphasis on histori-
cal features such as pain location, muscle tension, psy-
chologic stress, and headache triggers. In contrast, a
history of nausea in conjunction with headaches is
highly predictive of migraine.

4
 Chapter 1: Confusing one benign headache with another
Diagnosis
Migraine without aura.
Tip
Migraine often presents with features assumed to
be highly characteristic of tension-type headache.
Most patients consulting physicians for trouble-
some headaches have migraine and not tension-type
headache.
Migraine with or without aura?
Case
An 18-year-old woman sought a second opinion
because she had been told she should not use estrogen-
containing contraceptives – “the pill” – due to her diag-
nosis of migraine with aura. Instead she was prescribed
a progesterone-only pill but that had caused weight
gain and irregular periods and she recently stopped it.
She was not interested in an intrauterine device and
did not think she would be able to use barrier meth-
ods reliably. Most of her friends were taking “regu-
lar birth control pills” continuously and thus did not
have any withdrawal bleeding, and she wanted to do
this too. The patient’s headaches occurred only four or
five times a year. She wondered if she might be able
to use estrogen-containing oral contraceptives despite
her headaches, since she did not want to get pregnant.
What important piece of information is still
missing in this case?
It is not obvious that this patient’s diagnosis of
migraine with aura is correct. In fact, all we know
is that she has headaches once every few months. In
order to establish that she has migraine and/or aura,
we need to know the details of her headaches and any
accompanying features. In this case, the patient con-
firmed a diagnosis of migraine by describing unilat-
eral, pounding headaches with nausea that last half a
day when untreated and were severe enough to pre-
vent her from usual activities, including her usual
exercise routine. When asked if she has any warning
signs, or other things that occur in association with her
headaches, she mentioned that sometimes her vision
was blurry prior to a headache. She added that occa-
sionally “the pain is so bad I can’t see.” When ques-
tioned closely, she clarified this by saying that she actu-
Table 1.4. The Visual Aura Rating Scale (VARS)
Visual symptom characteristic Risk score
Duration 5–60 minutes 3
Develops gradually over 5 or more minutes 2
Scotoma 2
Zig-zag line (fortification spectrum) 2
Unilateral (homonymous) 1
Maximum VARS score 10
Migraine with aura diagnosis ࣙ5
Adapted from: Eriksen et al. The Visual Aura Rating Scale (VARS)
for migraine aura diagnosis. Cephalalgia. 2005;10:801–10, with
permission.
ally could see just fine, but shut her eyes tightly because
the pain was so bad. Even with further questioning she
did not report additional associated symptoms.
Does this patient have migraine with aura?
Aura is a focal neurologic event, which means that it
includes symptoms that can be attributed to dysfunc-
tion in a particular part of the brain. Aura symptoms
can be visual, sensory, motor, or mixed. Visual aura
is by far the most common form of aura. Most peo-
ple who have any form of aura will, at least occasion-
ally, also have visual aura. Common features of visual
aura are the scotoma, an area of decreased visual acuity
or visual loss (not seeing something that is there) or a
positive visual phenomenon (seeing something that is
not there) such as a zig-zag line. These areas of visual
loss or distortion are surrounded by areas of normal
vision. Figure 1.1 shows a typical scintillating scotoma
drawn by a patient who has migraine with aura, who
perceived that this scotoma was shimmering and pul-
sating. Often a scotoma will start as a small area in the
center of the visual field, and then expand and move to
the periphery of the visual field before fading away.
In migraine with aura, the aura typically precedes
the headache; symptoms begin and fade away gradu-
ally and do not last longer than an hour. Symptoms
also are unilateral (or, in the case of visual symptoms,
homonymous – which means they occur in only half of
the visual field). Once the aura begins to fade away, it
is usually quickly followed by a headache. Sometimes
aura can occur without a headache. Table 1.4 repro-
duces the Visual Aura Rating Scale, which is a method
of diagnosing visual aura. This scale assigns points for
the presence of certain aura symptoms; to diagnose
5
 Chapter 1: Confusing one benign headache with another
Figure 1.1 A typical scintillating migraine scotoma. Note the patient’s attempt to convey the shimmering sensation of movement and
vibration in the crescent-shaped, zig-zag visual phenomenon (fortification spectrum) that is drawn.
aura reliably requires a score of at least 5 of the pos-
sible 10 points.
Are estrogen-containing contraceptives
contraindicated in women who have
migraine with aura?
Migraine with aura is associated with an increased
risk of ischemic stroke and so is the use of exogenous
estrogens. The added risk of stroke with each of these
things individually is quite small, but it is higher in the
presence of additional risk factors, such as smoking or
increasing age. Although it is difficult to place abso-
lute numbers on these risks, authors of these studies
note the increase in risk is likely to be multiplicative
rather than additive. Because of these risks, guidelines
from a number of authoritative groups, including the
American College of Obstetrics and Gynecology, rec-
6
ommend against the use of estrogen-containing con-
traceptives in women who are over 35 and have any
type of migraine, or women who have migraine with
aura, regardless of age.
Discussion
This patient’s headaches met criteria for migraine but
the visual events she described were not consistent
with a diagnosis of aura. Thus, she has migraine with-
out aura and the use of estrogen-containing contra-
ceptives is not contraindicated. General visual blur-
ring and visual sensitivity, while commonly reported
by migraine patients, are not aura. The blurred vision
described by this patient is better thought of as part
of her headache prodrome. Prodromal events occur
before a headache but are not focal neurologic events.
Changes in mood, appetite, or concentration are
commonly reported migraine prodrome symptoms.
 Chapter 1: Confusing one benign headache with another
Distinguishing between migraine aura and migraine
prodromal or associated symptoms is important
because evidence that migraine with aura increases the
risk of stroke continues to mount.
Diagnosis
Migraine without aura.
Tip
Focal neurologic symptoms such as positive or neg-
ative visual phenomena or sensory disturbance are
required for a diagnosis of migraine aura. Since essen-
tially all patients with any sort of aura also have visual
aura, it is only necessary to establish a history of visual
aura in order to make a diagnosis.
Severe unilateral headaches in a man
Case
A 30-year-old man presented for management of clus-
ter headache diagnosed by another physician. He
reported an average of three headaches a month that
tended to occur towards the end of the month: “They
come in bunches. As soon as one is over I might
get another one a day or so later.” Headaches were
located over his forehead bilaterally and he described
them as throbbing, with occasional mild nausea. He
was not sure how long headaches would last with-
out treatment because for many years he had been
using subcutaneous sumatriptan as soon as headaches
began.
Is this history consistent with a diagnosis of
cluster headache?
Not all elements of the history in this case fit with clus-
ter headache. The bilateral nature of the pain is not typ-
ical of cluster headache, which is a strictly unilateral
headache, usually located behind an eye. The throb-
bing nature of the pain is more typical of migraine
than of cluster headache, in which the pain is usu-
ally described as sharp. The patient does report that
headaches come “in bunches,” but the period of sev-
eral days between attacks is not typical of true clus-
ter headaches, in which short headaches usually occur
daily or even several times a day. The patient’s response
to sumatriptan is not helpful in clarifying the diag-
nosis, since sumatriptan is effective for the treatment
of individual attacks of both migraine and cluster
headache.
Additional questioning about the features and
duration of individual headaches, as well as the pattern
of attacks over time, can distinguish migraine from
cluster headache. In this case, when questioned, the
patient reported that as a child he would occasionally
vomit with his headaches, and that they could last up
to a day. Both of these features are more consistent with
a diagnosis of migraine than with cluster headache.
Why was the diagnosis of migraine missed
in this patient?
The criteria for diagnosing migraine are the same for
men and women. Unfortunately, they do not fully
reflect differences between the sexes in the clinical pro-
file and presentation of migraine. Evidence from the
American Migraine Prevalence and Prevention Study
shows that, on average, men with migraine have fewer
clinical features of migraine than women with the
disorder. That is, men with migraine are less likely
than women with migraine to report nausea, vomit-
ing, photo or phonophobia. That does not mean they
do not have these symptoms, but rather that they have
fewer of these symptoms than women. Because doctors
rely on these characteristic historical features to make
the clinical diagnosis of migraine, men are at a disad-
vantage in receiving a correct diagnosis.
In this case, it seems likely that the patient’s physi-
cian correctly recognized that cluster headache is more
common in men and migraine is more common in
women. She failed, though, to realize that neither
headache type occurs exclusively in one sex.
Discussion
In addition to the fact that men with migraine report
fewer migraine-associated features than women, there
are other ways in which migraine may differ in
men compared with women. For example, men with
migraine report that, on average, their attacks are
shorter, less severe, and less disabling than migraine
attacks in women. Males with migraine also are not
exposed to the potent migraine trigger of monthly
changes in sex hormones as are females with the dis-
order, so there is no increase in migraine prevalence
at puberty in males. This is in contrast to the situa-
tion in females, where migraine prevalence increases
7
 Chapter 1: Confusing one benign headache with another
substantially at puberty and remains higher than the
prevalence in men even into old age. This suggests
that female hormones have an enduring effect on
migraine susceptibility. In addition to this lifelong
impact on disease risk, women with migraine also
experience periodic increases in migraine attack fre-
quency because of hormonal changes with the men-
strual cycle.
Although the prevalence of migraine in men is
lower than in women, migraine is an extremely com-
mon disorder in both sexes. By age 80, the cumulative
incidence of migraine in men reaches almost 18% –
meaning that almost one in five men will experience
migraine during his lifetime. As high as this number
is, though, it is certainly lower than the 44% lifetime
cumulative incidence of migraine in women. Thus it is
understandable that some physicians – and patients –
view migraine as a “woman’s disease.” Unfortunately,
the result is that when men seek care for their
headaches, clinicians may be less likely to consider
migraine as a diagnosis.
Diagnosis
Migraine without aura.
Tip
Migraine is more common in women than in men,
but it is highly prevalent in both sexes. Diagnosis of
migraine in men may be challenging because men with
migraine have fewer typical migraine symptoms than
do women.
Frequent, severe episodic headaches in
a woman
Case
A 45-year-old woman had been treated for many years
for a diagnosis of migraine. She treated individual
headaches with 10 mg of oral rizatriptan. Headaches
typically awakened her from sleep and were extremely
severe, sometimes associated with nausea. They lasted
two or three hours, so by the time the rizatriptan
became effective the headache was almost over. For
the last year her headaches had occurred nightly or
every other night, although prior to that she would
have headaches “only two or three months at a time
and I could deal with that.” With no break in her
headaches she reported being sleep-deprived and anx-
8
ious. She was taking 160 mg of long-acting propranolol
and 200 mg of topiramate daily. At the last visit she
reported that the medications were ineffective and that
she was “tired and can’t think straight. I am about to
lose my job.”
Has this patient developed chronic
migraine?
Chronic migraine is unlikely in this patient. Although
daily, her headaches are short, usually lasting three
hours or less. Another clue that this patient may
not have migraine is that the headaches have not
responded to aggressive treatment with the typi-
cally used migraine preventive treatments of propra-
nolol and topiramate. Of course, not all patients with
migraine improve with appropriate preventive treat-
ment, but failure to respond to migraine-specific ther-
apy may also suggest an alternative diagnosis. Most
features of this patient’s headaches are consistent with
a diagnosis of cluster headache and not migraine.
Additional questioning about the features and dura-
tion of individual headaches, as well as the pattern of
attacks over time, can distinguish the two disorders
(see Table 1.5).
In this case, the patient gave additional history
which further clarified the diagnosis. For ten years
before the onset of her daily headache she had just one
or two bouts of daily or near-daily headache each year.
Those periods of frequent headache lasted on aver-
age two months and seemed to come in the fall and
spring of each year. Individual headaches have always
been located behind the left eye and associated with
left-sided nasal congestion and tearing of the left eye.
Although they last only two to three hours, headaches
are extremely severe, “like someone is stabbing me in
the eye with a hot poker.” The patient is restless and
paces the floor during attacks. Her story is more con-
sistent with episodic cluster headache that has now
become chronic than with chronic migraine.
Why was cluster headache misdiagnosed in
this patient?
The presentation of cluster headache is highly charac-
teristic but the disorder is uncommon. In contrast to
migraine, it is more frequent in men than in women.
It is caused by dysfunction of central nervous system
pain control mechanisms and has distinctive circadian
and circannual features. Most physicians have never

Table 1.5. Distinguishing migraine from cluster headache
Pain features Migraine
Location Often unilateral over the temple or
forehead area but may be bilateral
Duration of attack 4–72 hours (adults)
Frequency of attacks Sporadic. Can “cluster” in bunches
but rarely follow the distinctive
pattern of true cluster headache
Associated features Nausea, vomiting, photo and
phonophobia
Sex ratio Females ⬎ males
Behavior during attack Quiet; prefer to lie quietly in a dark
room
Temporal features Attacks typically occur at random
and are not easily predictable
* According to ICHD-3 beta, all of these criteria must be met in at least five attacks in order to make a diagnosis of cluster headache.
seen or treated a patient with cluster headache and
may be especially likely to miss it in women, perhaps
because women with cluster headache are more likely
than men to have migrainous symptoms such as nau-
sea. Diagnostic delay is common in any case, however,
with one study showing that the median time from
onset to symptoms was three years, with a range of one
week to 48 years.
This patient’s partial response to a triptan medi-
cation may also have contributed to confusion about
the diagnosis, since many doctors think of triptans as
“migraine medications.” In fact, triptans are useful for
treating individual attacks of cluster headache as well
as migraine.
Discussion
Cluster headache is correctly diagnosed after the ini-
tial evaluation only 21% of the time. The most com-
mon incorrect diagnoses made in these patients are
migraine (34%) and sinusitis (21%). Migraine and
cluster can be differentiated on the basis of headache
duration, frequency, seasonality, triggering factors,
and pain behavior during a headache. The presence
of autonomic features is usually part of the presenta-
tion of cluster headache but is not strictly necessary for
diagnosis if the patient is agitated or paces during an
Chapter 1: Confusing one benign headache with another
Cluster headache
Strictly unilateral; typically highly localized to behind one eye
15 minutes to 3 hours*
Attacks can occur once every other day up to eight times a day (for more
than half of the time during an active cluster bout – headache frequency
may increase or taper slowly at the beginning or end of a bout)*
Agitation or restlessness OR one of the following seven symptoms or signs
must occur on the side of the headache: (1) eye redness or tearing; (2) nasal
congestion or runny nose; (3) edema of the eyelid; (4) sweating of the
forehead and face; (5) flushing of the forehead and face; (6) a feeling of ear
fullness; (7) decreased pupil size or ptosis*
Males ⬎ females
Agitated, restless
Attacks commonly occur at specific times of the day or night. Named for
the way they “cluster” together occurring daily or almost daily for 2- to
3-month bouts. In episodic cluster headache these bouts are separated by
periods of remission lasting at least a month; in chronic cluster headache
remissions do not occur or are shorter than a month
attack. Aura is very rarely seen in cluster headache but
should not rule out the diagnosis.
Preventive treatment of cluster headache differs
from that of migraine. Typical migraine preventive
drugs such as topiramate and propranolol are unlikely
to be helpful for cluster headache. In this case the
delay in accurate diagnosis has delayed institution of
appropriate preventive treatment aimed at reducing or
eliminating attacks of cluster headache. The mainstays
of prevention for cluster headache are verapamil or
lithium. There are no US Food and Drug Administra-
tion (FDA)-approved preventive treatments for clus-
ter headache, but clinical experience shows that one
or the other of these drugs, or occasionally the com-
bination, brings the disorder under control for most
patients.
The slow onset of action of oral triptans makes
them a poor treatment choice for most patients with
cluster headache. Subcutaneous sumatriptan, which
patients can self-administer via an auto-injector, has
a more rapid onset of action. It is the only triptan for-
mulation that is FDA approved for treatment of cluster
headache.
Diagnosis
Chronic cluster headache.
9
 Chapter 1: Confusing one benign headache with another
Tip
Cluster headache is more common in men but can also
occur in women. It is often missed in both sexes.
Headache with disturbing visual
perceptual alterations
Case
A 43-year-old woman reported she had experienced
bad headaches since childhood. In response to the
open-ended question “Does anything else happen with
your headaches?” she tearfully related symptoms that
“might sound crazy.” At age 11 she awoke one morn-
ing and, while still lying in bed, realized that her hands
did not feel “like they belonged to me.” When she held
them in front of her they looked long and twig-like,
not like normal hands. These perceptions disappeared
in a few minutes, but she then developed a severe,
unilateral headache with vomiting. Over the years she
has had many similar episodes of visual abnormality,
all followed by severe headaches that meet criteria for
migraine. Once while driving she noticed that a fence
and the trees behind it appeared weirdly distorted in
size and shape. This abnormality was limited to the
left side of her visual field but was still present when
she covered her left eye. The patient has discussed her
headaches with other physicians, but not her visual
symptoms, because of her fear that they might be inter-
preted as psychiatric in nature.
What conditions may be causing these
symptoms?
Bizarre visual illusions and distortions that affect the
apparent size, volume, shape, or position in space of
objects are described with the term “metamorphop-
sia.” Metamorphopsia is part of Alice in Wonderland
syndrome, thought to be a particular sort of migraine
with aura, but can also reflect structural eye disease
(usually retinal) and has been reported in patients
with idiopathic intracranial hypertension. Metamor-
phopsia is a common symptom in age-related macular
degeneration or other diseases that affect the macula.
Typically, patients will complain of “waves” or “bend-
ing” in objects known to be straight, such as door-
frames or roof lines. Careful examination of the retina,
as well as ancillary testing when necessary, includ-
ing Amsler grids or fluorescein angiography, can usu-
10
ally identify non-aura disorders that might be causing
metamorphopsia.
In this case, the symptoms were associated with
migraine and occur in consistent temporal relation
to the headaches. The patient was otherwise healthy,
and Alice in Wonderland syndrome is the most likely
diagnosis.
How should this patient be treated?
As is the case for more typical forms of aura, there
are no clinically available treatments that will specif-
ically treat the aura of Alice in Wonderland syndrome.
(Intravenous ketamine reportedly aborts aura in about
half of sufferers, but is not a practical approach to out-
patient therapy.) Rather, treatment is aimed at reduc-
ing the number of migraine episodes using typical
migraine preventive therapy, and also focuses treating
the pain of any headache that accompanies the aura.
Triptans and other vasoconstrictive agents are not con-
traindicated in this disorder or in migraine with more
typical forms of aura.
Discussion
This unusual form of aura is called “Alice in Wonder-
land syndrome” because of its similarity to the expe-
riences of Lewis Carroll’s fictional Alice in Wonder-
land. It was first described in 1955. The visual abnor-
malities in Alice in Wonderland syndrome are more
peculiar than those of typical visual aura. The visual
disturbance may also be associated with alterations in
the perception of time, or feelings of depersonalization
or derealization, which seem to be what the patient
in this vignette experienced during her first childhood
episode. Figures 1.2 and 1.3 depict an illustration of the
metamorphopsic visual distortions of this illness.
Alice in Wonderland syndrome is said to be more
common in children than adults. In our experience
this apparent difference in prevalence may stem from
the reluctance of adults to describe symptoms they fear
will result in stigmatization. Children may be less wor-
ried about this. In their 2008 book Headache in Chil-
dren and Adolescents, Winner et al. report that “The
children rarely seem frightened by these illusions and
relate the experience in enthusiastic detail. Witnesses
of the child’s event will either remark that the child
has an unusual, bemused look on the face or describe
the child changing body positions so that they can ‘get
under a low ceiling.’”
 Chapter 1: Confusing one benign headache with another

Figure 1.2 Normal vision.

Figure 1.3 Metamorphopsia in left

hemi-field of vision.

Diagnosis is reassuring for patients who may otherwise fear the

Alice in Wonderland syndrome – commonly thought
to be a form of migraine with aura.
Tip
Treatment for Alice in Wonderland syndrome does not
differ from that of typical visual aura with migraine.
It is important to recognize it because the diagnosis
symptoms mean they are “crazy.”
“Cluster migraine”
Case
A 27-year-old woman reported frequent headaches
characterized by retro-orbital pain, always on the

11
 Chapter 1: Confusing one benign headache with another
right, up to four hours in duration but usually shorter
because she had learned to treat the headaches imme-
diately with sumatriptan. The pain could become
severe quite quickly, and when the pain was at its worst
it was a 10/10 and had a stabbing quality. With the most
severe pain she also noticed tearing and redness of the
right eye. When the pain was milder she preferred to
be lying down, but at its worst, “it doesn’t matter what
I do, it just hurts.” There was associated photophobia
and some nausea but no aura. She had noticed that she
had times when her headaches occur very frequently,
up to twice a day, and other times when she would
have several weeks without a headache. In the past she
had been told she had “cluster migraines.” One of her
other physicians thought she had cluster headache and
started verapamil, which had improved the frequency
of headaches only mildly.
Are this patient’s autonomic features helpful
in making a diagnosis?
Autonomic features (lacrimation, conjunctival injec-
tion, forehead or facial sweating, miosis, ptosis, eyelid
edema, rhinorrhea, or nasal congestion) are a defin-
ing characteristic of the headaches classified as trigem-
inal autonomic cephalagias (TACs), including cluster
headache. The latest version of the headache classifi-
cation, ICHD-3 beta, however, does not require that
they be present in order to make a diagnosis of clus-
ter headache if the patient has the characteristic rest-
lessness or physical agitation that are seen in cluster
headache. ICHD-3 beta has also added a sensation of
fullness in the ear to the list of autonomic features that
may be seen in cluster headache patients.
Headache-associated autonomic signs or symp-
toms are not unique to cluster headache or other
TACs, however. They may be seen in association with
migraine headaches as well. In one population-based
study, one of four patients with migraine had unilat-
eral autonomic symptoms with at least some attacks.
One study also found that migraines occurring with
unilateral autonomic symptoms were more severe
than those occurring without. In a prospective study
comparing patients recruited from a headache cen-
ter with migraine headaches with those with cluster
headache, 56% of patients with migraine had cranial
autonomic symptoms with some of their headaches.
Thus, the presence of autonomic features in this case
does not necessarily indicate a diagnosis of cluster
12
headache, and is also compatible with a diagnosis of
migraine.
Is “cluster migraine” an appropriate
diagnosis in this patient?
The ICHD recognizes Cluster headache, one of the
TACs, and Migraine as two separate categories of
headaches. “Cluster migraine” is not a recognized term
in any edition of the ICHD, including ICHD-3 beta,
and this term often causes a great deal of confusion
among patients and providers.
Migraine sufferers sometimes hear the term “clus-
ter” and relate this to their experience of having inter-
vals of frequent headaches interspersed with times
when headaches are less frequent. In our experience,
these changes in headache frequency are commonly
the result of environmental factors such as changes in
lifestyle (a move, a new job), stress, changes in sleep
habits, or dietary changes. Intrinsic factors such as
hormonal changes associated with menstrual periods
may also contribute to cyclical changes in suscepti-
bility to migraine. All of these things may lower the
threshold for the development of migraine, resulting
in an increase in headache frequency. Another phe-
nomenon often leading to “runs” of migraine activity
is rebound headache, in which withdrawal from symp-
tomatic medications used to treat a previous headache
leads to another headache.
The patient described in this case meets criteria for
migraine without aura and not for cluster headache,
which was described earlier in this chapter. The term
“cluster migraine” is not a recognized diagnosis and
should be avoided.
Discussion
Autonomic activation during headache is a func-
tion of the trigeminal autonomic reflex. This reflex
occurs when nociceptive input from the trigeminal
system, as occurs during headache, stimulates the
trigeminocervical complex. This in turn stimulates
the superior salivatory nucleus, which gives rise to
autonomic fibers providing innervation to the head.
Autonomic symptoms are most commonly seen in
the TACs, but can also occur in migraine. Compared
to cranial autonomic symptoms in TACs, the symp-
toms in migraine are more likely to be bilateral, mild
or moderate in severity, and to occur inconsistently
with headache attacks. Lacrimation is the autonomic
 Chapter 1: Confusing one benign headache with another

symptom most commonly associated with migraines. Stabbing headaches in a migraineur

In contrast, the autonomic symptoms associated with
cluster headaches are unilateral 80% of the time and Case
almost always ipsilateral to the headache when they are
A 39-year-old woman presented to the office with a
unilateral.
“new headache type.” She had a long-standing his-
Distinguishing between “runs” of migraines and
tory of episodic migraine without aura. Headaches
a bout of true cluster headache can occasionally be
had increased in frequency over the last three years.
challenging. A very careful history should be taken
She attributed this to increased stress from having
with attention to headache duration, location of pain,
a second child four years ago and from increased
other associated features such as phono or photo-
responsibilities at work. Her migraines had gone from
phobia, and frequency. By ICHD criteria, migraine
occurring about once a week to as many as three per
and cluster should not overlap. Accurate diagnosis
week.
can be difficult when treatment has eliminated fea-
In the last four months, she had also developed
tures needed for diagnosis as, for example, might occur
severe stabbing or “shock-like” pains behind the eye,
with treatment that shortens the duration of migraine
in the temple, or in the parietal area on either side.
headaches. In these cases, a description of typical
These lasted only a few seconds at a time but some-
untreated headaches can be very useful.
times occurred in volleys of up to 10 or 20 closely
In contrast to migraine, cluster headache bouts are
spaced jabs of pain in the course of an hour. She had
often distinctly seasonal, possibly because of headache
some days without this new type of pain but more typ-
triggering by changes in day length or seasonally
ically the pain happened between one and ten times a
related changes in circadian rhythms. This seasonal
day. She had seen her dentist last week for a routine
periodicity is uncommon in migraine. Within indi-
checkup, and had been told her symptoms might be
vidual patients, the seasonality of cluster headache
due to trigeminal neuralgia. There were no autonomic
bouts may be stereotyped over many years. Some clus-
features and no provoking factors that she was able to
ter headache patients are able to predict months in
identify. She continued to have her typical migraine
advance when a cluster bout will occur.
without aura headaches and these had not changed in
It can also be helpful to determine if the patient
character or frequency. Her neurologic examination
has headaches outside of the identified “cluster” peri-
was normal.
ods. A patient with episodic cluster headache rarely has
any headaches at all outside of their cluster periods or
bouts, while patients with migraine will usually have
occasional isolated headaches even during their “good What is the differential diagnosis of sharp,
periods.” While this is a general rule, it is not always
true, however, since an occasional patient with chronic stabbing pain in a migraineur?
cluster headache (defined as cluster headaches occur- Several disorders can produce brief, stabbing head
ring for over a year without remission or with remis- pain. The differential diagnosis is worth knowing
sion for less than one month) will experience occa- because complaints of sharp, stabbing head pain are
sional isolated headaches. The true cluster headache remarkably common. Possible causes include (1) a
pattern, with periods of headaches occurring from one trigeminal or other neuralgia; (2) primary stabbing
every other day to eight per day followed by complete headache; or (3) one of two uncommon forms of ultra-
remission periods, is almost never seen in migraine. short unilateral stabbing headache in the TAC family
known as SUNCT (Short-lasting, Unilateral, Neuralgi-
Diagnosis form headache attacks with Conjunctival injection and
Tearing) or SUNA (Short-lasting Unilateral Neuralgi-
Migraine without aura.
form attacks with Autonomic features – with the auto-
nomic features required for diagnosis being identical
Tip to those required for a diagnosis of cluster headache).
Migraine headaches can present with autonomic fea- Both SUNCT and SUNA produce pain that is simi-
tures in up to half of patients. “Cluster migraine” is a lar in location to that of cluster headache but much
confusing term which should be avoided. shorter, in the range of 1–600 seconds.

13
 Chapter 1: Confusing one benign headache with another
Table 1.6. Clinical characteristics of primary stabbing
headache
Pain occurs as a single stab or may be a series of stabs
Individual stabs last only a few seconds and may recur with
irregular frequency
Stabs may be from one to many per day
Pain primarily occurs in the orbit, temple, or parietal areas, in the
distribution of the first division of the trigeminal nerve
No accompanying symptoms, including no autonomic
symptoms
The pain characteristics in this case are similar to
those of trigeminal neuralgia, but trigeminal neural-
gia typically does not switch sides or locations. Trig-
ger zones, areas of the face or mucosa where stim-
ulation reliably reproduces the pain, are frequently
but not always seen in trigeminal neuralgia. This
patient does not report a history of pain triggering.
In the absence of autonomic features, a TAC such as
SUNCT or SUNA is highly unlikely. Thus, the most
likely etiology for the stabbing pain in this patient
is primary stabbing headache. The clinical charac-
teristics of primary stabbing headache are listed in
Table 1.6.
Primary stabbing headache is more prevalent than
either trigeminal neuralgia or SUNCT/SUNA and is
very frequently seen in patients with migraine, where
it is often located in the same area where the migraine
pain is felt.
Does any further workup need to be done
for this new headache type?
Secondary causes of stabbing headaches have been
described in case reports, and include herpetic
meningoencephalitis, ischemic stroke, acute thalamic
hemorrhage, and meningioma. Posterior fossa lesions
may present with SUNA- or SUNCT-like symptoms.
In this case, the four-month duration of symptoms
without worsening, the nonfocal neurologic exami-
nation, and the relative youth and good health of
the patient are all reassuring. In our clinical expe-
rience, the development of stabbing headache in a
migraineur often accompanies worsening of the pri-
mary headache. However, stabbing headaches present-
ing in older patients, with progressive worsening of
symptoms, an abnormal neurologic examination, or
failure to respond to appropriate treatment are all sit-
14
uations requiring a workup for secondary causes. If
this patient had presented acutely with a new stab-
bing headache and associated neurologic symptoms,
further evaluation would be warranted.
Discussion
Primary or idiopathic stabbing headache has been
known by many names over the years, including “jabs
and jolts” and “ice-pick” headaches. The pathophysi-
ology is not well understood. It occurs in about 2%
of the general population, but is even more preva-
lent in patients with other primary headache disorders.
Up to 40% of migraineurs and 27% of patients with
tension-type headache may have comorbid primary
stabbing headache, and it has also been described in
patients with hemicrania continua (one of the TACs).
In these cases, the stabs tend to occur in the loca-
tion most affected by the underlying primary headache
type. The frequency of attacks can vary from a single
stab a few times a year to up to 50 per day. In some
cases the stabs start out infrequently and progress to
volleys of stabs lasting minutes to hours. Stabbing
headaches occurring outside the distribution of the
trigeminal nerve have also been described with some
regularity.
Classically, primary stabbing headache is con-
sidered an indomethacin-responsive headache and
indomethacin is first-line treatment when treatment
is indicated. If the stabs are infrequent, reassurance
about their benign nature may be all that is needed.
About 30% of patients may not improve with indo-
methacin. Case reports have also described improve-
ment with gabapentin, celecoxib, and melatonin in
those who did not respond to or could not tolerate
indomethacin. Although not a phenomenon described
in the literature, our clinical experience is that
occasional stabbing headaches in migraineurs often
improve with appropriate treatment of the migraine
itself. This approach may spare the patient treatment
with indomethacin, which like all anti-inflammatory
drugs can have serious gastric side effects.
In this case, the patient’s underlying migraine
headaches were increasing in frequency due to envi-
ronmental factors. Because of the increased frequency,
she was started on amitriptyline for prevention of
migraine. At her follow-up visit two months later,
the migraines had returned to their previous weekly
pattern and the stabbing headaches had completely
resolved.
 Chapter 1: Confusing one benign headache with another
Diagnosis
Primary stabbing headache in the setting of migraine
without aura.
Tip
Primary stabbing headache is commonly associated
with migraine and does not necessarily require a
workup for secondary headache if there are no accom-
panying neurologic features.
Chronic continuous headache with
acute onset
Case
A 29-year-old right-handed female presented for eval-
uation of a “life-altering headache.” There was no fam-
ily history of migraine and she recalled no headache
problems during high school or college. On Septem-
ber 8 (about four months prior to consultation), she
had awakened with a headache that never resolved. She
recalled nothing unusual around that time, specifically
no serious physical or emotional trauma or illness that
had been associated with the onset of headache. She
did recall having a mild upper respiratory infection
several days before the headache began. She described
the headache as a pressure sensation behind the left
eye, usually 3/10 in severity but reaching 5/10 at its
worst, always present from the time she woke up in
the morning to the time she went to sleep. This pain
had been unremitting since onset. She had mild nausea
with the headache but otherwise no associated symp-
toms or autonomic features and the headache did not
wake her from sleep.
Evaluation had included a normal magnetic reso-
nance angiogram and venogram of the brain; normal
CT angiogram; normal lumbar puncture with opening
pressure of 150 mm cerebrospinal fluid (CSF); normal
routine laboratory studies; negative Lyme titers; and
normal antinuclear antibody (ANA) level, thyroid-
stimulating hormone (TSH) level, erythrocyte sedi-
mentation rate (ESR), and C-reactive protein (CRP)
level. She had been diagnosed with migraine but failed
to improve with aggressive trials of typical migraine
preventive drugs, except for a brief reduction in pain
severity with a course of oral prednisone. She had ini-
tially been unable to work and had moved back in with
her parents. Recently, however, she had returned to
work after several months away because her disability
Table 1.7. Clinical characteristics of new daily persistent
headache
Head pain for more than 3 months that is constant
Unremitting from onset or within 24 hours of onset
No completely characteristic features, although migrainous
features such as photophobia, phonophobia, or nausea are
frequently described
Female predominance with F:M ratio 1.4–2.5:1
Onset of pain is clearly remembered by the patient, although
fewer than half of patients recall a triggering event
benefits had expired. She reported being frustrated by
her symptoms and inability to plan activity.
What is the differential diagnosis in
this case?
The differential diagnosis for unremitting headache
with acute onset is lengthy. Most of the potential
causes are secondary forms of headache in which the
head pain is due to some underlying process. For this
reason, an extensive workup for secondary causes of
headache (as was done in this case) is necessary. In this
case, the patient had appropriate testing but no sec-
ondary cause of headache had been identified.
A number of primary headache disorders can pro-
duce the clinical scenario of acute onset, unrelenting
headache, and should be considered in this patient.
These include hemicrania continua, chronic migraine,
chronic tension-type headache, and new daily persis-
tent headache (usually referred to by its initials of
NDPH).
One highly characteristic feature of NDPH is that
many patients (about half) recall the precise date when
the headache started. This is so characteristic of the ill-
ness that the diagnostic criteria for NDPH state that
the onset must be “distinct and clearly remembered.”
In our experience many patients also note the exact
time of onset with great precision, for example “My
headache began at 5:02 p.m. on September 8, 2003.”
Although the headache may pursue a “stuttering”
course initially, it quickly becomes constant. In fact,
diagnostic criteria require that the headache become
constant within 24 hours of onset (see Table 1.7 for
other clinical characteristics). When the onset of a
refractory headache is so clearly recalled, and in the
absence of abnormal tests or examinations, a diagno-
sis of NDPH is far more likely than another primary
headache disorder.
15
 Chapter 1: Confusing one benign headache with another
What advice can be provided to the patient
about the natural history of NDPH, and is
any further workup required?
Many patients are relieved to be given a name for their
condition. By the time a patient receives this diagno-
sis, they have usually had an extensive evaluation and
some have developed a conviction that doctors have no
idea what is wrong and have “given up.” Clarification
that the condition is recognized, classified, and studied
can itself be reassuring. Patients are sometimes disap-
pointed by the lack of good quality information about
the natural history of the disorder, and by the lack of
identified treatments for it. Providers often share their
frustration!
The clinical features of NDPH are highly vari-
able, and it can resemble migraine or tension-type
headache. In the absence of validated treatments for
NDPH, treatment is usually aimed at the phenotype
of the particular patient’s headaches. Thus, patients
whose headaches have features of migraine, such as
nausea, may be treated as this patient was, with drugs
typically used for migraine. A few specific agents have
been reported in the literature as benefitting small
numbers of patients. These include the antiepilep-
tic drugs topiramate and gabapentin, the tetracycline
derivative doxycycline, corticosteroids, nerve blocks,
and mexiletine.
Unfortunately, treatment of this disorder is often
unsuccessful. It is still useful to follow the patient reg-
ularly and to consider periodically whether other eval-
uation is warranted. It may be useful, for example,
to consider evaluation for an underlying sleep disor-
der. One other test to consider in patients who have
not had it is a lumbar puncture. This can identify dis-
orders of CSF pressure, which in our experience can
mimic almost any form of primary headache, includ-
ing NDPH. A good therapeutic relationship with a
patient can also prevent them from trying unproven
or dangerous therapies out of desperation.
Discussion
NDPH was first described in 1986 and is currently clas-
sified as one of the “other” primary headache disorders
(other than migraine, tension-type, and the TACs, that
is). It is a diagnosis used with some trepidation by most
clinicians, since it is essentially a clinical description of
the patient’s presentation without clear evidence of any
pathophysiologic explanation.
16
Table 1.8. Secondary causes to rule out in case of apparent
new daily persistent headache
Vascular:
– Carotid or vertebral artery dissection
– Cerebral venous thrombosis
– Giant cell arteritis
Nonvascular:
– Disorder of CSF pressure, either high or low
– Meningitis
– Sphenoid sinusitis
– Intranasal (contact point) headache (pain caused by
contact of intranasal structures such as nasal septum and
nasal turbinate)
– Cervical facet disease
– Intracranial neoplasm or mass lesion
– Medication overuse headache
In addition to more commonly recognized causes
of secondary headache that are described in Table 1.8,
studies currently suggest two other possible patho-
physiologic mechanisms for NDPH. The first is a local-
ized inflammatory process of the central nervous sys-
tem, perhaps precipitated by a viral illness of some
kind. The second theory is that the headache might
result from a connective tissue process that leads to
joint laxity and cervical spine hypermobility. Some
authors have suggested a typical physiognomy for
NDPH patients, classically a tall, thin female with a
long neck, joint laxity, and hypermobility in the cer-
vical spine.
NDPH appears to be rare. In epidemiologic stud-
ies, patients with NDPH are usually grouped together
with other people who have “chronic daily headache,”
and they account for about 10% or less of such patients
in most studies. Early descriptions of NDPH empha-
sized that it was often self-limited and could remit
after months to years. Most headache specialists, how-
ever, see patients in whom the disorder persists and is
resistant to treatment. It is more common in females,
with a sex ratio of about 2:1 and an earlier age of
onset in females. Although initial reports of NDPH
described headache with tension-type characteristics,
recent case series suggest that more than half the time
the headache may have associated migrainous features.
Because of this, the ICHD-3 beta criteria for the dis-
order mention that the pain “lacks characteristic fea-
tures, and may be migraine-like or tension-type like, or
have elements of both.” Similarly, no features are spec-
ified by the diagnostic criteria for the location of the
headache or the quality of the pain.
As with the patient in this case, the onset of NDPH
in many patients has been associated with trigger
 Chapter 1: Confusing one benign headache with another
Table 1.9. Suggested workup for apparent new daily
persistent headache
Neuroimaging: brain MRI with and without gadolinium, MRV
Intra- and extracranial MRA
Lumbar puncture with opening pressure
events, particularly a prior infectious, usually viral, ill-
ness, a stressful experience, or even an extracranial sur-
gical procedure. It is difficult to evaluate whether these
things are causally linked to headache or whether such
events are recalled more easily by patients or clini-
cians who are eagerly searching for a cause of disabling,
refractory headaches. In addition to any testing that is
indicated by a particular patient’s clinical presentation,
Table 1.9 lists investigations that should be strongly
considered to rule out head trauma or disorders of CSF
pressure that can sometimes masquerade as NDPH.
Diagnosis
New daily persistent headache.
Tip
Acute onset of unremitting headache is characteristic
of NDPH, but many secondary headaches present sim-
ilarly. Although NDPH can have features of migraine,
tension-type headache, or both, it is a distinct disorder.
Strictly unilateral headache
Case
A 46-year-old woman presented with a 20-year his-
tory of disabling headache that had not responded well
to treatment. She had been diagnosed with chronic
migraine due to severe headaches located on the right
side of her head only. When queried specifically about
associated symptoms of nausea, vomiting, photo and
phonophobia, the patient endorsed only occasional
mild nausea. She also reported “shadow headaches,”
by which she meant that in between episodes of severe
headache she had continuous milder pain, also on the
right side of the head. Her neurologic examination was
normal, as was neuroimaging done in the last year.
She brought past medical records that documented
prior unsuccessful treatment trials with a large number
of preventive drugs for migraine, including botulinum
toxin injections. The doses and duration of these tri-
als appeared to have been adequate. Triptans were
never effective for headache exacerbations, but large
Table 1.10. Clinical characteristics of hemicrania continua
r Unilateral, unremitting head pain lasting more than 3 months,
with mild baseline pain but periodic exacerbations of severe
pain
r During exacerbations
Either: agitation or restlessness OR
one of the following seven symptoms or signs must occur on
the side of the headache:
(1) eye redness or tearing;
(2) nasal congestion or runny nose;
(3) edema of the eyelid;
(4) sweating of the forehead and face;
(5) flushing of the forehead and face;
(6) a feeling of ear fullness;
(7) decreased pupil size or ptosis
r Response to indomethacin is complete at therapeutic doses
doses of ibuprofen gave some relief. She had been told
to discontinue this, however, because of worries that
her daily use of the drug might be causing medica-
tion overuse headache. Her only other medication was
over-the-counter pseudoephedrine, which she took for
“a problem with my sinus on the right.”
What additional question might clarify the
diagnosis in this case?
It is understandable that a diagnosis of migraine has
been made in this case. Migraine is the most common
form of disabling headache in women of childbearing
age, and it is often unilateral. Furthermore, it becomes
chronic in some patients, who often have mild to mod-
erate constant baseline pain with superimposed exac-
erbations of headache, just as this patient describes.
When pressed, this patient also reported occasional
nausea, another feature that may suggest migraine. It is
easy to overlook the curious fact that her symptoms all
appear to be right-sided. There is, however, an alterna-
tive diagnosis that is compatible with her continuous,
unilateral headache: hemicrania continua, a primary
headache with autonomic features.
The clinical criteria of hemicrania continua are
listed in Table 1.10. In the new version of the headache
diagnostic classification, it is now considered one of
the trigeminal autonomic cephalgias (formerly it was
considered with the “other” primary headaches). Like
cluster headache and the other TACs, hemicrania con-
tinua is a side-locked, strictly unilateral headache with
associated autonomic features. It differs from the other
TACs, however, in that it is continuous. It is also
uniquely responsive to a particular nonsteroidal anti-
inflammatory medication, indomethacin. Response to
17
 Chapter 1: Confusing one benign headache with another
this drug is required to make a firm diagnosis of
hemicrania continua. (Unfortunately, this diagnostic
requirement means that a definite diagnosis cannot be
made in patients who present with a clinical picture
compatible with hemicrania continua but cannot take
or do not tolerate indomethacin.)
With the possibility of this alternative diagnosis
in mind, the most useful additional question for the
patient described in the case becomes “Have you ever
had pain on the left side of the head?” In this case, the
patient reports that she has never had left-sided pain.
Further questioning revealed that this nasal conges-
tion was right-sided, and that her husband had told
her that her right eye was sometimes “droopy.” Upon
further discussion, the patient stated that these symp-
toms had never come up because no one had ever asked
before.
What treatment should be tried next?
The patient’s additional history makes a diagnosis
of hemicrania continua likely, but a definite diag-
nosis requires a complete response to therapeutic
doses of indomethacin. The reported effective dose
of indomethacin in hemicrania continua ranges from
50 to 300 mg/day. This dosing regimen is also
commonly used in patients with primary stabbing
headache, another indomethacin-sensitive primary
headache syndrome. Common practice is to begin
with indomethacin 25 mg orally three times a day
for three days; if the patient tolerates this but has no
headache improvement the dose is increased to 50 mg
three times a day for three more days, and again if
no response to 75 mg three times a day for a further
three days. The authors of ICHD-3 beta recommend
that doses of up to 225 mg/day should be tried “if
necessary.”
There are no good treatment alternatives for
patients who cannot use indomethacin. Patients
may occasionally experience a partial, less complete
response to other anti-inflammatory agents, but most
patients who cannot tolerate indomethacin also have
difficulty tolerating other anti-inflammatory drugs.
Discussion
This patient reported a long history of headaches
diagnosed as migraine that have been refractory to
appropriate treatment for migraine. This is a common
story in patients who ultimately receive the diagno-
sis of hemicrania continua. Any history of side-locked,
18
continuous headache should prompt consideration of
hemicrania continua, but this is especially true if the
patient is partially responsive to nonsteroidal anti-
inflammatory treatment.
The temporal pattern of hemicrania continua is
low-grade baseline headache with occasional exacer-
bations. Patients may initially report only the more
severe headaches and neglect to mention the lower-
grade baseline headache because it is less bothersome
to them. This is one reason hemicrania continua may
be misdiagnosed as migraine. An additional clue to the
correct diagnosis was the nasal congestion for which
she took daily decongestants, which upon question-
ing was ipsilateral to the headache, as was the pre-
viously undisclosed ptosis. Patients with hemicrania
continua may also report a sense of something being
stuck in the eye, such as an eyelash or a piece of sand,
sometimes called a “foreign body sensation.” This is
another symptom patients frequently do not report
spontaneously.
When headache treatment fails, a number of pos-
sible explanations may be considered: (1) incorrect
diagnosis; (2) exacerbating factors have been missed;
(3) treatment has been inadequate; or (4) unrealis-
tic expectations or comorbidity exist. In this case,
additional and open-ended questioning about the
headache history provided important clues to correct
diagnosis and treatment.
Diagnosis
Hemicrania continua.
Tip
Hemicrania continua is easily confused with chronic
migraine. Important characteristics, including accom-
panying autonomic features and the side-locked char-
acter of the pain, may not be volunteered by the
patient.
Further reading
Migraine vs. tension-type headache
Calhoun AH, Ford S, Millen C, et al. The prevalence of neck
pain in migraine. Headache. 2010;50(8):1273–7.
Diener HC, Pfaffenrath V, Pageler L, et al. Headache
classification by history has only limited predictive value
for headache episodes treated in controlled trials with
OTC analgesics. Cephalalgia. 2009;29(2):188–93.
 Chapter 1: Confusing one benign headache with another
Fernandez-de-las-Penas C, Madeleine P, Caminero AB,
et al. Generalized neck-shoulder hyperalgesia in chronic
tension-type headache and unilateral migraine assessed
by pressure pain sensitivity topographical maps of the
trapezius muscle. Cephalalgia. 2010;30(1):77–86.
Jensen R. Pathophysiological mechanisms of tension-type
headache: a review of epidemiological and experimental
studies. Cephalalgia. 1999;19(6):602–21.
Smetana GW. The diagnostic value of historical features in
primary headache syndromes: a comprehensive review.
Arch Intern Med. 2000;160(18):2729–37.
Tepper SJ, Dahlof CG, Dowson A, et al. Prevalence and
diagnosis of migraine in patients consulting their
physician with a complaint of headache: data from the
Landmark Study. Headache. 2004;44(9):856–64.
Wober C, Holzhammer J, Zeitlhofer J, Wessely P,
Wober-Bingol C. Trigger factors of migraine and
tension-type headache: experience and knowledge of the
patients. J Headache Pain. 2006;7(4):188–95.
Diagnosing migraine with aura
Eriksen MK, Thomsen LL, Olesen J. The Visual Aura Rating
Scale (VARS) for migraine aura diagnosis. Cephalalgia.
2005;10:801–10.
Migraine in men
Stewart WF, Linet MS, Celentano DD, Van Natta M, Ziegler
D. Age and sex-specific incidence rates of migraine with
and without aura. Am J Epidemiol. 1991;134(10):1111–
20.
Stewart WF, Wood C, Reed ML, Roy J, Lipton RB, AMPP
Advisory Group. Cumulative lifetime migraine
incidence in women and men. Cephalalgia. 2008;28(11):
1170–8.
Cluster headache in women
Rozen TD, Fishman RS. Female cluster headache in the
United States of America: what are the gender
differences? Results from the United States Cluster
Headache Survey. J Neurol Sci. 2012;317(1–2):17–28.
Rozen TD, Fishman RS. Cluster headache in the United
States of America: demographics, clinical characteristics,
triggers, suicidality, and personal burden. Headache.
2012;52(1):99–113.
van Vliet JA, Eekers PJ, Haan J, Ferrari MD, Dutch RUSSH
Study Group. Features involved in the diagnostic delay
of cluster headache. J Neurol Neurosurg Psychiatry.
2003;74(8):1123–5.
Alice in Wonderland syndrome
Podoll K, Robinson D. Migraine Art – The Migraine
Experience from Within. Berkeley, California, North
Atlantic Books. 2009; 85–146.
Todd J. The syndrome of Alice in Wonderland. Can Med
Assoc J. 1955;73(9):701–4.
Winner P, Lewis D, Rothner AD, eds. Headache in Children
and Adolescents. Lewiston, NY, BC Dekker, 2008.
“Cluster migraine”
Barbanti P, Fabbrini G, Pesare M, Vanacore N, Cerbo R.
Unilateral cranial autonomic symptoms in migraine.
Cephalalgia. 2002;22(4):256–9.
Lai TH, Fuh JL, Wang SJ. Cranial autonomic symptoms in
migraine: characteristics and comparison with cluster
headache. J Neurol Neurosurg Psychiatry. 2009;80(10):
1116–19.
Obermann M, Yoon MS, Dommes P, et al. Prevalence of
trigeminal autonomic symptoms in migraine: a
population-based study. Cephalalgia. 2007;27(6):504–9.
NDPH
Goadsby PJ. New daily persistent headache: a syndrome not
a discrete disorder. Headache. 2011;51(4):650–3.
Robbins MS, Evans RW. The heterogeneity of new daily
persistent headache. Headache. 2012;52(10):1579–89.
Rozen TD. New daily persistent headache: clinical
perspective. Headache. 2011;51(4):641–9.
Young WB. Expert Commentary on New Daily Persistent
Headache. Headache. 2011;51(4):654–6.
Hemicrania continua
Lipton RB, Silberstein SD, Saper JR, Bigal ME, Goadsby PJ.
Why headache treatment fails. Neurology. 2003;60(7):
1064–70.
Rossi P, Tassorelli C, Allena M, et al. Focus on therapy:
hemicrania continua and new daily persistent headache.
J Headache Pain. 2010;11(3):259–65.
19
 Chapter
Mistaking primary headache for another
2 condition
In Chapter 1, we discussed pitfalls that can lead to
confusing one type of primary headache disorder with
another. Primary, nondangerous headaches may also
be confused with or incorrectly attributed to multi-
ple other medical conditions. It is of course possible
for patients to have two separate forms of headaches
(e.g. allergy-related headache and migraine), but this
situation is probably not as common as many doc-
tors assume. Some medical conditions, for example
hypertension, are commonly but mistakenly assumed
to be frequent causes of headache. Other conditions,
such as sinus disease or temporomandibular joint
dysfunction, may exacerbate an underlying primary
headache disorder but are less commonly its sole
cause. And finally, for some disorders, such as Arnold
Chiari malformations or pituitary lesions, it may
be impossible to determine with certainty whether
the primary headache is related to the structural
lesion.
Most of the medical conditions incorrectly
assumed to produce headache are common, and
under the right circumstances all of them can be the
true cause of headaches. Their prevalence, however,
means that often their association with headaches is
due to chance. This matters because assumptions of
causality may lead to overly aggressive treatment of
the disorder assumed to be causing the headaches.
Such treatment will not only be ineffective for the
headaches but may also lead to other side effects or
problems. A good example is sinus surgery that is
done in the mistaken belief that migraine headaches
are due to sinus disease. We see many patients whose
migraines continue to be a problem but who also suffer
from persistent post-surgical pain or dysesthesias.
In this chapter, we highlight the pitfalls that can
lead to an incorrect diagnosis of headache due to
another condition when the actual problem is a pri-
mary headache such as migraine.
20
“Sinus headache”
Case
A 55-year-old man reported a history of headaches
since age 15. These were initially intermittent but
had gradually worsened over the last several years
and become constant. The episodic headaches he
had when he was younger had been unilateral;
severe; lasted up to 24 hours; and were associated
with photophobia, phonophobia, and nausea. He had
been diagnosed with “cluster and vascular tension
headache.”
He had been referred to an otolaryngologist
because of frequent episodes of bilateral facial pain
and rhinorrhea. An MRI scan showed mild mucosal
thickening (Figure 2.1) in the maxillary sinuses bilat-
erally, and he was told that his headaches were prob-
ably due to sinus disease. After several rounds of
antibiotic treatment failed to produce improvement in
headaches, he had undergone a total of seven surgi-
cal sinus procedures over the course of 20 years in an
unsuccessful attempt to treat headaches.
At the time of consultation he reported bilat-
eral pain over the maxillary sinuses and forehead
area, as well as the posterior head and neck. He
rated the pain as 5 or 6 on a 0–10 scale at base-
line, with daily exacerbations up to 8 or 9 lasting five
to six hours that were associated with photophobia,
phonophobia, osmophobia, and nausea. The headache
increased when he bent over and he noted a sensa-
tion of pressure and fullness in the maxillary regions
bilaterally.
The patient’s exacerbations of pain responded
well to symptomatic treatment with sumatriptan,
but trials of typical preventive medications for
migraine did not reduce the frequency or intensity of
headache.

Figure 2.1 An MRI showing mucosal thickening in both maxillary
sinuses. Source: http://commons.wikimedia.org/wiki/File:Brain MRI
112010 rgbca.png.
How is chronic sinus disease diagnosed?
The term rhinosinusitis is preferred to sinusitis because
the middle turbinate is often involved in sinus dis-
ease. A clinical practice guideline from the American
Academy of Otolaryngology – Head and Neck Surgery
(AAOHNS) defines acute bacterial rhinosinusitis
(ABRS) as up to four weeks of purulent nasal drainage,
accompanied by nasal obstruction, facial pain/
pressure/fullness, or both. Recurrent acute rhino-
sinusitis is diagnosed when four or more episodes of
ABRS separated by symptom-free periods occur in
one year. Chronic rhinosinusitis is defined as 12 weeks
of two or more of the following symptoms: muco-
purulent drainage, nasal obstruction/congestion,
facial pain/pressure/fullness, or decreased sense of
smell, as well as documented inflammation as evi-
denced by either purulent mucus or visible mucosal
edema, nasal polyps, or radiographic imaging show-
ing paranasal sinus inflammation. Table 2.1 lists
criteria for distinguishing chronic rhinosinusitis from
recurrent bouts of acute disease.
In this case we are not provided with enough infor-
mation to be certain whether the patient’s diagnosis of
Chapter 2: Conditions that mimic primary headache
Table 2.1. Clinical features of chronic vs. recurrent
rhinosinusitis
Recurrent acute
Chronic rhinosinusitis rhinosinusitis
More than 3 months of a Four or more episodes
combination of purulent nasal per year of acute sinusitis
drainage, nasal obstruction, with clearing of
facial pressure/pain, or reduced symptoms and findings
sense of smell in between
AND
Inflammation documented by
direct observation or imaging
sinusitis was correct, but it seems reasonable to assume
that the patient had at least recurrent acute bacterial
rhinosinusitis if not chronic rhinosinusitis in addition
to the primary headache syndrome.
Won’t imaging clarify the diagnosis of
sinusitis?
In this situation, diagnostic confusion is not usually
resolved by diagnostic testing. It is important to note
that there is considerable expert consensus that abnor-
malities on CT scan are not sufficient to make a diag-
nosis of rhinosinusitis. Some imaging abnormalities
commonly assumed to indicate rhinosinusitis are not
specific; for example, mucosal thickening may be seen
in up to 40% of the asymptomatic population. Most
expert guidelines suggest that a patient must meet clin-
ical criteria for a diagnosis of sinusitis first, after which
imaging is considered to be confirmatory rather than
suggestive. Thus, abnormalities on sinus imaging or
endoscopy that are consistent with sinusitis are not
by themselves sufficient to assume that they are caus-
ing headache. CT is, however, particularly helpful in
determining any anatomic abnormalities which may
be exacerbating recurrent rhinosinusitis or chronic
rhinosinusitis.
What sinus-related headaches do headache
specialists recognize?
The International Classification of Headache Disor-
ders (ICHD)-3 beta recognizes two types of headache
related to sinus disease. The first is headache attributed
to acute rhinosinusitis. The diagnostic criteria for
this form of headache require clinical, endoscopic,
or imaging evidence consistent with rhinosinusitis. In
addition, however, some evidence of causality must be
present in order to attribute any associated headache
21
 Chapter 2: Conditions that mimic primary headache

to the sinus abnormalities. Evidence that sinus abnor- Table 2.2. Clinical characteristics of headaches attributed to
rhinosinusitis and disorders of the nasal cavity
malities are causing headache can come in the form
of a temporal relationship with the development of Sinus Headache due to
or any change in headache, or by exacerbation of the (rhinosinusitis) disorders of the
headache with pressure over the paranasal sinuses. If headache nasal cavity
the physical sinus abnormalities are unilateral, an ipsi- Pain location Frontal headache If imaging or physical
lateral headache also stands as evidence of a causal radiating to face, ears, abnormalities are
or teeth unilateral, headache
relationship, according to these new criteria. Inter- should also be
estingly, the requirement that headaches be frontally unilateral. Otherwise,
located or accompanied by pain in the face, ears, or no specific location is
characteristic
teeth has been removed from the new version of the
Imaging Direct or imaging Direct or imaging
classification. evidence of changes evidence of a
ICHD-3 beta also recognizes headache attributed consistent with hypertrophic or
to chronic or recurring rhinosinusitis, commenting chronic or acute inflammatory process
sinusitis in the nasal cavity
that while the association of headache with chronic
sinusitis has been controversial, new evidence appears Aggravating/ Headache develops Pain often resolves
alleviating or changes in with local application
to support a connection. Imaging or endoscopic evi- features conjunction with the of anesthetic to the
dence of current or past infection or inflammation in clinical course of contact point region
the sinuses is required, along with at least two other sinus inflammation
things that support a causal connection. These can
be either the development of or change in headache
character that parallels the degree of sinusitis, the
onset of headache in conjunction with the disorder, can likewise have serious complications. We see many
or exacerbation of the headache with pressure over patients in our practice who have developed chronic
the paranasal sinuses. As with headache attributed to pain problems or dysesthesias after having many sinus
acute sinusitis, a unilateral headache is also grounds to operations.
assume a causal connection when associated with ipsi- Many symptoms assumed to indicate a sinus ori-
lateral imaging abnormalities. gin of pain are not necessarily specific to rhino-
The ICHD-3 beta appendix also includes proposed sinusitis and can be seen in migraine. These include
criteria for a diagnosis of headache attributed to dis- a pain location in the face or area over the sinuses,
order of the nasal mucosa, turbinates, or septum, for changes in pain that correlate with the weather or sea-
which evidence is limited. This headache is hypothe- sons, and pain associated with rhinorrhea, sinus pres-
sized to occur due to irritation or inflammation related sure, or nasal congestion. Fluctuations in barometric
to a hypertrophic or other process in the nasal cav- pressure associated with changes in weather are a fre-
ity. It resolves fully after application of topical anes- quently reported migraine trigger, for example, but are
thetic or changes in severity in relation to gravitational often interpreted as a trigger for sinus problems. Many
or positional changes. Table 2.2 summarizes the clin- patients who treat presumed “sinus headaches” with
ical characteristics of headaches due to sinus or nasal decongestants report that this treatment is modestly
disease. effective and assume that this proves the headaches
are due to sinus problems. Decongestants, however,
are vasoconstrictors and furthermore are often sold
Discussion in combination with simple analgesics such as aspirin
As with the patient in the vignette, migraine is or acetaminophen. This combination of medications
commonly mistaken for a sinus problem. Patients is, not surprisingly, sometimes helpful for migraine
may receive repeated courses of powerful antibiotics headaches and thus response to this treatment does not
to treat the presumed sinus infection. Overuse of confirm the presence of sinus headaches. The major-
antibiotics is a serious public health problem, and ity of patients using these medications for presumed
can cause harm to individual patients as well. Sinus “sinus headache” will have an even better response
surgery performed in the mistaken belief that a to migraine-specific drugs. In one study, for exam-
patient with migraine has headaches due to sinusitis ple, the majority of self-diagnosed patients with “sinus

22

headaches” experienced greater than 50% of reduction
in pain with triptan use.
In the Sinus, Allergy, and Migraine study (SAM),
100 consecutive participants who responded to a ques-
tionnaire and believed that they had sinus headache
were enrolled. After a detailed history and physical
exam, only 3% were classified as having headache due
to rhinosinusitis. The remainder met diagnostic crite-
ria for migraine with or without aura (52%), probable
migraine (23%), various forms of chronic migraine or
other primary headaches (12%). In another study of
almost 3000 patients with self- or physician-diagnosed
“sinus headaches,” 80% of the patients presenting with
“sinus headaches” met diagnostic criteria for migraine
with or without aura. It is thus abundantly clear that
migraine is often mistaken for sinusitis.
Rhinosinusitis and migraine may also coexist,
however, complicating the diagnosis. The majority of
patients who attribute their headaches to sinus dis-
ease do have prior diagnoses of allergic rhinitis, acute
rhinosinusitis, and (to a lesser extent) chronic rhino-
sinusitis, although the accuracy of those diagnoses is
not clear. In the SAM study, a third of patients expe-
rienced chronic cranial autonomic symptoms whose
exacerbations triggered migraine headaches, indicat-
ing to the authors that seasonal allergic rhinitis could
at times trigger migraine.
Diagnosis
Migraine without aura and chronic rhinosinusitis.
Tip
A diagnosis of headache attributed to rhinosinusitis
must be made clinically and then confirmed by imag-
ing or endoscopy. Treatments such as antibiotics or
surgery that are given for mistaken diagnoses of sinusi-
tis expose patients to harm and prevent the use of more
effective migraine-specific treatment.
Chronic headache after Lyme disease
Case
A 28-year-old woman with a prior history of episodic
migraine presented for evaluation of a new and differ-
ent type of headache, which she described as a con-
stant, generalized pressure with a severity of 4/10 on a
scale of 0–10. It was not associated with nausea but she
was sensitive to light and noise. She still had her typi-
Chapter 2: Conditions that mimic primary headache
cal, intermittent migraine headaches, which occurred
on average once a week and responded well to suma-
triptan. She was also taking six to eight tablets daily of
a butalbital-containing medication to control her daily
headache pain.
The patient suspected her new headache was a
symptom of chronic Lyme disease. She lived in an
endemic area and had noticed a tick bite four years
ago. She was immediately and empirically treated with
doxycycline. A friend, however, told her that Lyme dis-
ease often is not cured by short courses of antibiotic
treatment and advised that she see a Lyme specialist.
That physician had been treating her with regular high
doses of vitamins and intravenous ceftriaxone through
a percutaneous indwelling catheter. On review of sys-
tems, the patient had a large number of symptoms that
she attributed to chronic Lyme disease.
Her neurologic examination was normal. A brain
MRI and lumbar puncture were also normal. Cere-
brospinal fluid (CSF) studies showed a normal protein
and no antibodies to Borrelia burgdorferi.
How common is headache in patients with
Lyme disease and is it likely that this
patient’s headaches were due to persistent
neurologic infection?
Headache is common in patients with Lyme disease
but by no means universal. About half of patients
with new positive Lyme serology will report headache
and headache is more common in patients with other
symptoms of central nervous system and systemic
involvement. In patients who only had positive CSF
serology and headache, the headache features could
resemble either migraine or tension-type headache.
Rarely, headache will be the only presenting feature
of Lyme disease, which is usually not diagnosed until
lumbar puncture shows characteristic CSF abnormali-
ties of high protein, lymphocytic pleocytosis, and Bor-
relia burgdorferi-specific intrathecal antibodies.
It is, however, unlikely that this patient has persis-
tent neurologic infection or headaches due to Lyme
disease. She did not report the characteristic ery-
thema migrans rash of Lyme disease and was treated
promptly with appropriate antibiotic therapy for her
tick bite. She has never had peripheral nervous sys-
tem complications or CSF findings consistent with
Lyme neuroborreliosis. Rather, her long-standing his-
tory of episodic migraine and daily use of combination
23
 Chapter 2: Conditions that mimic primary headache

Figure 2.2 A deer tick of the sort that can transmit Lyme disease.

analgesics make medication overuse headache and

chronic migraine far more likely diagnoses than Lyme
disease.

What are the symptoms of chronic Lyme Figure 2.3 The characteristic erythema migrans rash of Lyme
disease. Source: http://en.wikipedia.org/wiki/File:Erythema
neuroborreliosis and how is it treated? migrans - erythematous rash in Lyme disease - PHIL 9875.jpg.
Chronic Lyme neuroborreliosis usually results from
untreated or unsuccessfully treated Lyme disease
which can become disseminated and affect the brain
The diagnosis of early, uncomplicated disease is usu-
and nervous system. Neurologic complications usually
ally based on clinical features such as a history of tick
appear a month or later after the tick bite. They include
exposure and the characteristic erythema migrans rash
Bell’s palsy, painful meningoradiculitis, or meningi-
(Figures 2.2 and 2.3). Fever, headache, joint pains,
tis. The latter is a rare complication of Lyme dis-
fatigue, and other constitutional symptoms may occur.
ease, possibly more common in children, and often
Serologic tests for Lyme disease are often negative in
associated with papilledema. Late complications of
this early stage of the disease, and are not required for
Lyme neuroborreliosis can include cerebral vasculitis,
diagnosis: the erythema migrans rash itself is diagnos-
progressive encephalitis, or encephalomyelitis. Lyme
tic. Most clinical guidelines agree that early infection
encephalitis characteristically produces evidence of
responds well to short courses of oral antibiotics such
nonspecific parenchymal involvement on neuroimag-
as doxycycline.
ing. In the absence of parenchymal involvement, oral
Subjective symptoms that persist six months or
antibiotic treatment is usually considered satisfac-
more after treatment of Lyme disease are sometimes
tory for this stage of the disease, although some
termed “post-Lyme disease syndrome.” Headache is
patients may continue to have troublesome symptoms
often a prominent symptom in such patients. How-
and require treatment with intravenous ceftriaxone or
ever, it seems unlikely that the patient in this case ever
penicillin G.
had Lyme disease. Instead, she has a long history of
episodic migraine, and her chronic headaches may be
Discussion due to medication overuse or represent the develop-
The spirochete Borrelia burgdorferi, which is trans- ment of chronic migraine. Most authorities agree that
mitted to humans through the bite of deer ticks, is there is little good evidence that lengthy treatment
endemic in the United States. Infection risk is high- with antibiotics improves outcomes in patients with
est in wooded areas of New England, the northern post-Lyme disease syndrome. In fact, many harmful
Pacific coast, and the area around the Great Lakes. consequences of such prolonged treatment have been

24

reported, including biliary damage as a result of pro-
longed use of ceftriaxone.
Diagnosis
Medication overuse headache; probable chronic mi-
graine without aura.
Tip
Persistent Lyme disease is an unlikely cause of
headache in patients who do not have objective find-
ings of central nervous system involvement.
Headache in the setting of
temporomandibular abnormalities
Case
A 42-year-old woman was seen in a headache clinic for
evaluation of chronic headache. She reported having
headaches since high school and described herself as
someone who “always has headaches.” The headaches
were initially intermittent but had become daily over
the last three years. They were worse in the morn-
ings. She reported generalized head pain but the pain
was most severe around the temples and jaw bilater-
ally. The pain was described as dull and achy and rated
4 on a scale of 0–10. When severe, the pain would
become throbbing and was associated with photopho-
bia, phonophobia, osmophobia, nausea, and some-
times vomiting. Stress, anxiety, and worsening jaw ten-
sion seemed to make the headaches worse, and they
also seemed worse around her menstrual periods.
Recently the patient had become aware that she
clenched her teeth constantly. After evaluation by
a dentist she was diagnosed with displacement of
the temporomandibular (TMJ) joint (Figure 2.4), a
form of temporomandibular disorder (TMD). She also
received diagnoses of bruxism and myofascial pain
in the muscles of mastication. She was provided with
a night guard to prevent nighttime bruxism, but her
headaches persisted. She suspected that TMJ dysfunc-
tion was the cause of the chronic headache and had
purchased several custom-made oral appliances from
her dentist, aimed at reducing bruxism and improving
her pain. Because the cost of these appliances was not
covered by insurance, however, the patient had paid for
them out of pocket. Her headaches continued, though,
and surgery on the TMJ had been advised. However,
before proceeding she wanted a second opinion.
Chapter 2: Conditions that mimic primary headache
Figure 2.4 The temporomandibular joint. Source: http://en.
wikipedia.org/wiki/File:Gray309.png.
How likely is this daily headache to be due
to pathology of the TMD?
It can be difficult to make a diagnosis of headache
attributed to TMD because many people grind or
clench their teeth and occasional jaw pain is common.
ICHD-3 beta requires that the diagnosis can only be
made when there is clinical or radiologic evidence of
pathology of the jaw or TMJ or associated structures.
Furthermore, some evidence of causation is required
in the form of development or change of the headache
in conjunction with any pathologic changes, or exacer-
bation of pain by active or passive jaw movements or
provocative maneuvers. If the joint pathology is uni-
lateral, the headache pain must be ipsilateral to the site
of the pathology.
A number of historical or examination features can
be useful when trying to assess the possibility of TMD
pathology. These include the presence of localized jaw
pain or physical findings such as impaired jaw range
of motion, joint sounds with movement (e.g. clicking),
and muscle and joint tenderness to palpation.
In this case we are not provided with the details
of the initial dental examination. On examination
in the headache clinic, however, the patient did
not give a clear history of pain development that
correlated closely with demonstrated TMJ pathol-
ogy. Furthermore, there was no impairment of jaw
opening and minimal pain on palpation over the
25
 Chapter 2: Conditions that mimic primary headache
Table 2.3. Clinical features of headache attributed to
temporomandibular disorder
Imaging or clinical evidence of pathology in the TMJ or nearby
structures or masticatory muscles
Evidence of a causal link between headache and this pathology,
as demonstrated by onset or worsening of pain in association
with the pathology, or worsening of pain with active or passive
movements of the jaw or with provocative maneuvers including
pressure on masticatory muscles or the TMJ
temporomandibular joint. Many details of the patient’s
history seemed more compatible with a diagnosis of
chronic migraine, such as the associated headache fea-
tures of nausea, vomiting, and phono and photopho-
bia. She was advised to postpone treatment of the
TMJ and was treated with more aggressive preventive
therapy for migraine. Her headaches became episodic
and were more easily controlled with migraine-specific
therapy.
Discussion
Jaw pain is common and many patients seen in spe-
cialty headache practice have already been evaluated
and treated by a dentist for presumed TMJ pathology.
It is difficult to estimate the true prevalence of TMDs.
One large review suggested that they occur in roughly
10% of the population, mostly in middle-aged adults.
Like migraine, they are more common in females than
males. They may therefore coexist with migraine in
many patients, but this does not mean they are a causal
or contributing factor to headache problems. ICHD-3
beta criteria for a diagnosis of headache attributed to
TMD are summarized in Table 2.3.
Diagnosis
Chronic migraine.
Tip
Familiarity with the presentation and findings in TMD
as distinct from migraine can help prevent confusion
when migraine masquerades as TMD.
Postpartum headache
Case
A 24-year-old woman developed acute headache six
hours after a normal spontaneous vaginal delivery, for
which she had epidural anesthesia. She had a history of
26
Table 2.4. Selected causes of postpartum headache
Primary causes:
Migraine
Other primary headaches
Secondary causes:
Vascular:
Ischemic stroke
Hemorrhagic stroke, including subarachnoid hemorrhage
Venous sinus thrombosis
Reversible cerebral vasoconstriction (RCVS)
Arterial dissection
Vasculitis
Hypertension/Posterior reversible encephalopathy
syndrome (PRES)
Nonvascular:
Preeclampsia/eclampsia
Idiopathic intracranial hypertension
Post-dural puncture headache
episodic migraine with aura that had improved during
the pregnancy.
After delivery she had the acute onset of a severe
bifrontal headache, associated with nausea and blurred
vision, which she identified as similar to her prior
migraines but much more severe. The headache and
nausea seemed to worsen when she was sitting up. Her
neurologic examination showed mild diffuse hyper-
reflexia but was otherwise normal.
Because of the acute onset of headache an
evaluation, including noncontrast head CT and
MRI/MRA/MRV with contrast, was done and was
negative. Urinalysis showed no proteinuria and her
blood pressure was 132/85 mm Hg. A parenteral anal-
gesic medication was administered. By the time the
diagnostic testing was completed her headache had
started to improve and she declined a recommended
lumbar puncture.
What is the differential diagnosis of
postpartum headache?
The differential diagnosis for postpartum headache
is lengthy. Selected causes are listed in Table 2.4.
They include both benign primary headaches such
as migraine, and dangerous secondary causes of
headache such as cerebral venous thrombosis. A
detailed headache history and thorough neurologic
examination can be helpful in differentiating between
primary and secondary causes of headache, but a
high suspicion of secondary causes is appropriate.
Postpartum headaches that are similar to a patient’s
pre-existing headaches, particularly if the headaches

persisted during pregnancy, are probably more likely
to be benign. Likewise, a nonfocal neurologic exami-
nation is reassuring. In this case, the finding of hyper-
reflexia is of unclear significance. Furthermore, her
report of an acute headache more severe than her usual
headaches is concerning.
Should further diagnostic testing be done?
If so, what?
Headache characteristics that should prompt workup
for secondary headache in the postpartum period are
similar to the “red flags” that warrant workup in other
settings. These include a new headache or change
in an established headache pattern, changes in men-
tal status, new focal neurologic deficits, uncontrol-
lable vomiting, or intractable headache. A history of
primary headache disorder such as migraine is not
always reassuring in the postpartum setting because
migraine is associated with an increased likelihood
of several dangerous causes of headache, including
peripartum stroke, preeclampsia, and angiopathy or
reversible cerebral vasoconstrictive syndrome.
Appropriate diagnostic investigation depends on
the suspected cause of secondary headache. Imaging
is frequently needed to assess for the possibility of
intracranial vascular problems. A head CT and lum-
bar puncture can be performed to rule out intracere-
bral or subarachnoid hemorrhage, and MRA/MRV are
appropriate to evaluate for vasculitis, vasoconstrictive
syndromes, or cerebral venous thrombosis. Angiog-
raphy may be needed when cerebral vasoconstriction
or aneurysm are strongly suspected. An MRI of the
brain with contrast may show meningeal enhance-
ment in cases of post-dural puncture headache, and a
lumbar puncture may show low opening pressure. If
preeclampsia is suspected, monitoring for proteinuria,
hyperreflexia, and hypertension is warranted.
In this case, the initial workup for causes of sec-
ondary headache was negative. Because the patient’s
headaches started to resolve after the MRI/MRA/MRV
and this testing was negative, a lumbar puncture was
deferred. She was monitored in the Mother and Baby
Unit for an additional three days without recurrence of
headache, and felt well at the time of discharge.
Discussion
About one-third of women experience headache in the
postpartum period, and both primary and secondary
postpartum headaches are more frequent in women
Chapter 2: Conditions that mimic primary headache
with a prior history of migraine. Other factors asso-
ciated with an increased risk of postpartum headache
are known dural puncture, previous headache history,
and multiparity.
Secondary causes are responsible for 25–50% of
postpartum headaches; these are discussed elsewhere.
Among the primary headache disorders that produce
postpartum headache, recurrence of migraine is prob-
ably the most frequent. In one study of 1000 women
with postpartum headache, migraine or another pri-
mary headache disorder was identified as the etiology
in 75% of cases. Migraine may reappear within a week
to one month after delivery and has been attributed to
causes such as declining estrogen levels, sleep disrup-
tion, and stress.
Even when a diagnosis of migraine is made in a
patient with postpartum headaches we believe it is
prudent to avoid vasoconstrictive medications such as
triptans because the postpartum period in migraineurs
may be a situation of heightened susceptibility to the
vasoconstrictive effects of triptans.
Diagnosis
Migraine without aura.
Tip
A high index of suspicion for dangerous causes of post-
partum headache is appropriate, but the most common
cause of postpartum headache in a known migraineur
is migraine.
A middle-aged man with low-lying
cerebellar tonsils
Case
A 49-year-old male was evaluated for frequent
headache. He reported a family history of migraine.
He had no history of childhood headache or of peri-
odic symptoms related to migraine such as motion
sickness. Headaches had begun in his mid 30s. They
were infrequent and the pain was generalized and
moderate in intensity. The headaches could last
for days and generally did not respond to simple
analgesics. They were attributed to sinusitis.
When the patient was in his late 30s the headaches
became more severe and were associated with migrain-
ous features such as nausea. He sought treatment
and was diagnosed with migraine. He was prescribed
27
 Chapter 2: Conditions that mimic primary headache
Figure 2.5 A sagittal T1 MRI image showing moderate tonsillar
descent.
oral zolmitriptan 5 mg. This effectively aborted indi-
vidual attacks of headaches but headache frequency
increased and by his mid 40s the patient had two to
three episodes of severe headaches weekly. In addition,
he noted gradual onset of a constant low-grade head
and posterior occipital pressure, which he described
as “like a tourniquet” or tight band around his head
and neck. The pain was not postural. There were no
abnormalities on neurologic examination. An MRI
of the head showed mild cerebellar tonsillar descent
(Figure 2.5) into the foramen magnum.
The patient was seen by a neurosurgeon, who
believed that his symptoms were related to a Chiari 1
malformation (CM1) and recommended surgery. The
patient sought a second opinion from another neuro-
surgeon, who strongly advised against surgery and
referred him for headache consultation.
At the time of his visit to the headache center
the patient was experiencing three headache exacer-
bations weekly, each lasting one to two days, super-
imposed on the generalized tight sensation that was
always present. The severe headaches were present
when he awakened. They were described as throb-
bing, generalized, and associated with photophobia
and nausea. The patient was taking frequent over-the-
counter medications to treat his headaches and was
occasionally using a butalbital combination medica-
28
Table 2.5. Clinical and MRI characteristics of headache
associated with Chiari malformation, type I
Headache that is occipital or suboccipital or precipitated by
Valsalva maneuvers or lasts less than 5 minutes OR headache that
has developed or changed in conjunction with a CM1 OR
headache associated with posterior fossa dysfunction, indicated
by lower cranial nerve or cervical spinal cord dysfunction or
otoneurologic or brainstem symptoms such as dizziness, vertigo,
oscillopsia.
Demonstration of a CM1 by MRI:
ࣙ5 mm caudal descent of the cerebellar tonsils OR
ࣙ3 mm caudal descent of the cerebellar tonsils plus posterior
fossa crowding manifested by:
compression of the posterolateral cerebellar CSF spaces
reduced height of the supraocciput
increased slope of the tentorium
kinking of the medulla oblongata
Table 2.6. Clinical characteristics of cough headache
Headache precipitated only by coughing, straining, or Valsalva
maneuvers
Sudden in onset
Location not specified
Lasts 1 second to 60 minutes
tion prescribed by another physician. He was work-
ing but had been unable to exercise because of the
headache. He had gained 30 pounds in the preced-
ing year. His sleep was fragmented and he reported
daytime somnolence. His neurologic examination was
normal. A lumbar puncture showed a normal opening
pressure and no CSF abnormalities.
How can headache attributed to a Chiari I
malformation be diagnosed?
Headache related to a CM1 is characteristically located
in the occipital region of the head and is intermittent
rather than constant. It is often provoked by maneu-
vers or activities that temporarily raise CSF pressure,
such as coughing or sneezing. It generally does not
have features more characteristic of migraine or other
primary headaches, such as associated nausea or pho-
tophobia. Table 2.5 lists the clinical and imaging fea-
tures of this disorder.
CM1 is easily confused with cough headache,
which is described in Table 2.6. Cough headache is a
primary headache disorder in which headache is pre-
cipitated by cough or other Valsalva-type maneuvers,
but is not associated with identifiable structural abnor-
malities. It is a diagnosis of exclusion, and should be
made only after imaging has been done to assess for
possible abnormalities of the posterior fossa.

Roughly 40% of patients who present with appar-
ent “cough headache” in fact turn out to have CM1.
Other reported secondary causes of headache precipi-
tated by cough or Valsalva include carotid or vertebro-
basilar diseases and cerebral aneurysms. Thus, neuro-
imaging plays an important role in differentiating
secondary from primary causes of cough headache.
CM1 can also present as a more protean chronic
headache, with or without exertional features, usu-
ally located in the posterior occipital or suboccipi-
tal regions. If associated with other neurologic signs
and symptoms, the diagnosis is usually not particularly
challenging. Often, however, headache is either the ini-
tial or only manifestation of the condition.
A diagnosis of symptomatic CM1 does not seem
very likely in the patient described in this case, despite
the documented cerebellar tonsillar descent. He does
not describe headache in association with cough and
his clinical presentation is more characteristic of
migraine. Cerebellar tonsillar descent or “brain sag”
can occur in patients with spontaneous intracranial
hypotension, so a lumbar puncture is recommended
in patients who have any cerebellar tonsillar descent
to assess the possibility of a CSF leak.
What treatment should be recommended to
this patient?
The patient likely had a past history of headaches com-
patible with a diagnosis of episodic migraine with-
out aura. Unusual presenting features were the late
age of onset and the initial nondescript features of
the headache. Later, though, a more typical pattern of
migraine emerged and his headache pattern was more
easily recognizable as a transformation from episodic
to chronic migraine. Although the posterior occipital
neck pressure he reported might suggest a secondary
headache cause such as CM1, there were few other
features in the history or examination to suggest this
diagnosis. Additionally, when carefully measured, the
degree of tonsillar descent on the patient’s MRI was less
than 3 mm, meaning that he did not meet radiologic
criteria for a CM1.
At times the historical features of a headache pat-
tern do not allow a clear diagnosis to be made and fur-
ther testing such as diagnostic neuroimaging may be
warranted. If misinterpreted, however, imaging may
confuse the situation further. This patient was advised
that although it was possible the MRI findings were
related to his headache, it was much more likely that
Chapter 2: Conditions that mimic primary headache
this was an incidental finding and that he had a pri-
mary headache disorder for which medical manage-
ment was indicated.
The patient improved with a brief course of
oral steroids and discontinuation of daily analgesics.
Amitriptyline and topiramate were added as pre-
ventive agents and a triptan drug was restarted for
headache exacerbations. He was evaluated and found
to have sleep apnea, for which treatment was started.
At a follow-up visit, he considered his headaches well
controlled on this regimen and had been able to
resume daily exercise.
Discussion
A Chiari type 1 malformation is a cerebellar anomaly
in which there is descent of the cerebellar tonsils to
at least 3–5 mm below the foramen magnum. This
abnormality often occurs alone but can also be associ-
ated with a spinal cord syrinx, hydromyelia, or hydro-
cephalus. Although generally considered to be a con-
genital lesion, symptoms often do not begin until
adulthood. This delay may be due to altered CSF
dynamics with aging or to changes in connective tis-
sue that occur over time. Many people with docu-
mented cerebellar tonsillar descent – up to a third – are
asymptomatic.
Descent of the cerebellar tonsils is a frequent inci-
dental finding on MRI performed for other reasons.
It is fairly common, with an incidence estimated to
be around 0.5% of the population and a female to
male ratio of 3:2. There is no clear correlation between
the degree of cerebellar tonsillar descent and the clin-
ical severity of headache. Thus, radiologic findings
alone should almost never prompt surgical interven-
tion. Rather, the clinical context of the findings must be
carefully considered. Headache related to CM1 is often
located in the occipital or suboccipital regions and is
often worsened by cough Valsalva, postural change, or
bending over.
MRI correlates of CM1 have been characterized
based on large case series of affected patients. Herni-
ation of the cerebellar tonsils 3–5 mm below a line
drawn between the tip of the clivus and the rim of the
foramen magnum is the most consistently used mea-
surement to determine the diagnosis. Lesser amounts
of descent are considered to represent merely ton-
sillar ectopia, and this is generally thought to be
asymptomatic. Other MRI features may also be
present, including elongation of the tonsils, caudal
29
 Chapter 2: Conditions that mimic primary headache
Table 2.7. Classification of Chiari malformations
Malformation Description of congenital
type malformation
Type I Elongation of the tonsils and the medial parts
of the inferior lobes of the cerebellum into
cone-shaped projections, which accompany
the medulla oblongata into the spinal canal
Type II Displacement of the parts of the inferior
vermis, pons, and medulla oblongata
together with elongation of the fourth
ventricle (most cases are associated with
spina bifida)
Type III Herniation of the entire cerebellum into the
cervical canal. This is associated with severe
neurologic deficits
Type IV Cerebellar hypoplasia
displacement of the brainstem and fourth ventricle,
crowding of the posterior fossa with obliteration of
the subarachnoid space, and bulbo-cervical kinking,
an increased angle formed by the brainstem and cervi-
cal spine at their margin. Figure 2.5 illustrates some of
these findings. The features of other degrees of Chiari
malformation are described in Table 2.7.
Diagnosis
Chronic migraine; tonsillar ectopia.
Tip
The clinical context of headache occurring in the
setting of low-lying cerebellar tonsils must be care-
fully considered. Caution is warranted in making a
diagnosis of headache attributed to CM1, in order
to avoid exposing patients to possible unnecessary
surgery which can cause serious complications.
Cluster headache presenting as
a dental problem
Case
A 49-year-old female was evaluated for a 20-year his-
tory of episodic left-sided headache. Headaches typi-
cally occurred daily for periods of one to two months
during the spring every year, although she could go for
several years without having any pain episodes. During
her one- to two-month bouts of headache, she experi-
enced headaches located behind the left eye. They were
associated with tearing and the pain radiated to the left
30
cheek or teeth. The pain was described as sharp, stab-
bing, and excruciating: “definitely a 10/10, worse than
childbirth.” Individual episodes of pain lasted up to 30
minutes and usually occurred at night.
The patient had seen a dentist and undergone
removal of her wisdom teeth with no benefit. She
was then diagnosed with TMJ disorder and provided
with a night guard. Her headache pattern seemed
to improve after that, but the next year headaches
recurred. Later she returned to the dentist. Several
fillings were replaced and a suspected diseased tooth
was removed. With each procedure she would seem to
improve transiently before experiencing a return of her
prior headache pattern. During a typical headache the
patient paced the room, noting that it was better for
her to walk than to remain in bed with a headache.
Her primary care physician had suggested that she
might have cluster headache and referred the patient
for evaluation. At the time of the neurologic evaluation
she reported her headaches were unresponsive to treat-
ment with opioid analgesics and her most recent bouts
of headache had been separated by only six months.
She was frustrated and commented: “I’ve been search-
ing for an answer for 20 years. It’s only on the left
side.”
What is the most likely diagnosis in
this case?
This patient does meet diagnostic criteria for a diagno-
sis of episodic cluster headache. Despite this, an accu-
rate diagnosis was not made until 20 years after her
headaches began. Cluster headache is characterized by
a severe unilateral orbito-temporal pain lasting from
15 minutes to 3 hours associated with ipsilateral auto-
nomic features such as tearing, nasal congestion, eyelid
edema, ptosis, or conjunctival edema.
Although cluster headache is more common in
men, it does occur in females. Recent epidemiologic
data suggest that the sex ratio is less lopsided than
originally suspected. Currently the male:female ratio
is estimated to be about 2:1.
Bouts of episodic cluster headache typically last
2–12 weeks and are separated by pain-free periods of
at least 2 weeks but typically longer. Cluster headache
is termed chronic when a remission is absent for a year
or more or is present but of short duration, less than 14
days in length.
In this vignette, though the pattern meets crite-
ria for a diagnosis of episodic cluster headache, the

patient’s bouts are becoming more frequent. It is pos-
sible that this is the beginning of a conversion from
episodic to chronic cluster headache. It is not uncom-
mon for physicians or patients to attribute the uncom-
mon and unilateral pattern of cluster headache to local
disease in the sinuses or teeth and direct inquiry to
those disorders.
Was the dental work this patient had
indicated?
It is unlikely that the dental work this patient had was
in fact necessary. A dentist who is unfamiliar with the
diagnosis of cluster headache can easily attribute clus-
ter headache pain to a local dental process. The uni-
lateral nature of the pain, as well as the fact that pain
is often felt in the jaw area, means that patients fre-
quently seek dental evaluation. Studies indicate that
almost half of cluster patients will have visited a
dentist for evaluation before the diagnosis of clus-
ter headache is eventually made. Unfortunately, many
undergo repeated, invasive dental procedures in an
attempt to treat the pain. As with the patient described
in this vignette, it can be years before an accurate diag-
nosis of cluster headache is made. This is unfortunate
because medical therapy for cluster headache is often
remarkably effective.
Discussion
For a variety of reasons, episodic cluster can be a chal-
lenging diagnosis and a delay in diagnosis from onset
of symptoms of up to five years is described, though the
delay may be longer in females with cluster. Episodic
cluster will at times present to the dentist and the diag-
nosis can be missed. In one study just fewer than half
of patients eventually diagnosed with cluster presented
for dental evaluation as part of the initial evaluation of
their pain and many of these patients received unnec-
essary or inappropriate dental management for their
symptoms.
The current International Classification of
Headache Disorders (ICHD) criteria for cluster
include an orbital, supraorbital, and/or temporal
localization for the pain. However, ipsilateral radia-
tion of the pain to the face and teeth is not unusual in
cluster. It is well documented that cluster may in part
present with a midface localization or radiation of
pain, and this is thought perhaps the main explanation
for diagnostic confusion among dental practitioners.
Chapter 2: Conditions that mimic primary headache
A revision of the ICHD criteria for cluster to include
this localization has been suggested as a possible step
to mitigate the confusion.
Worsening or triggering of a cluster headache pat-
tern after dental procedures has also been reported,
explained in part by deafferentation of pain fibers in
the region of the dental procedure leading to trigger-
ing of brainstem and spinal cord pain networks. The
possibility that a dental procedure might precipitate
a cluster attack further underlines the need to elimi-
nate diagnostic confusion and avoid unnecessary pro-
cedures in these patients.
Given the pain severity and associated disability of
cluster headache, it is important for dental personnel
to recognize the features of this headache pattern; they
may well be the first to see and diagnose the patient.
Those in dentistry should redouble their efforts to ren-
der an accurate diagnosis and to avoid unnecessary
and inappropriate dental treatments. Timely manage-
ment in order to minimize patient disability is the
goal.
Diagnosis
Episodic cluster headache.
Tip
Cluster headache is a unilateral pain disorder that is
frequently mistaken for a dental problem. Familiar-
ity with the characteristic pattern of cluster headache
is important to avoid costly and unnecessary dental
procedures.
An older woman with focal neurologic
deficits but no headache
Case
A 71-year-old woman was seen in the emergency
department. She reported that five hours ago, while
reading a magazine, she suddenly developed a visual
disturbance. She found the type on the magazine page
blurry and could not make out the individual letters.
She was able to see the face of her husband. After a
few minutes she noticed a thin bright white line in the
upper part of her visual field in the right eye. These
symptoms continued for 20 minutes, when she devel-
oped numbness of her left cheek that gradually spread
to the side of her nose and corner of her mouth. Her
tongue was not numb. Five minutes later her husband
31
 Chapter 2: Conditions that mimic primary headache
noticed that she was unable to express herself and that
her speech consisted of nonsense words. The visual
changes lasted 40 minutes, the speech problems for 10
minutes and the numbness for an hour. She had no
associated headache.
The patient had experienced a similar episode one
month earlier. She had been seen in the emergency
department and had a workup including brain imag-
ing, Holter monitor, and carotid studies, all of which
were negative. She was diagnosed with a transient
ischemic attack and instructed to take 81 mg of aspirin
daily. She had osteoarthritis and hypertension that was
well controlled on lisinopril and was otherwise well.
She was not a smoker and her cholesterol levels were
normal.
In the past she had experienced periodic throb-
bing, unilateral headaches preceded by neurologic
symptoms similar to those she had now. Her pre-
vious headaches had been diagnosed as migraine
but she had not had any severe headaches for the
last 20 years. After hearing about the patient’s most
recent event, the neurology resident on call diag-
nosed a second transient ischemic attack and was con-
cerned that this had occurred despite aspirin ther-
apy. She wondered whether the patient should be
placed on additional antiplatelet therapy, a statin, or
anticoagulated.
This patient had a negative workup a month
ago. Should she be reinvestigated now or
could this be a benign process?
The patient probably does not need additional test-
ing or investigation for this second episode of tran-
sient neurologic deficits, but it is easy to understand
the neurology resident’s anxiety. The patient is in an
age group where transient ischemic attacks and strokes
are common. She also gives a clear history of neu-
rologic deficits, although the reversible nature of her
symptoms is more suggestive of a transient ischemic
attack than a stroke. However, her symptoms have
been fully evaluated with no suggestion of a throm-
botic or embolic cause. In fact, this patient’s symptoms
are likely to be what the famous neurologist C. Miller
Fisher termed “late-life migraine accompaniments.”
Fisher’s “rules” for the diagnosis of late-life
migraine accompaniments (Table 2.8) are still useful
clinically, and help to put the case of the patient in the
vignette into clearer context.
32
Table 2.8. Clinical characteristics of “late-life migraine
accompaniments” From C. Miller Fisher
r Most common aura is visual, followed by paresthesias,
then aphasia/dysarthria, then (rarely) paralysis
r Symptoms usually build, one upon another
r There may be a spread or “march” of symptoms
r Progression from one symptom to the next is common
r ࣙ2 similar episodes required for confirmation
r Duration of each individual symptom is usually 15–25
minutes
r Symptoms may or may not be followed by headache
r Generally indicates a benign course
r Exclude other conditions. Requires normal imaging
What is the epidemiology of late-life
migraine accompaniments, and should they
be treated?
An analysis of data from the Framingham Study
showed that migrainous visual accompaniments in late
life are not rare. In over 2000 queried subjects, 1.23%
reported migrainous visual symptoms. The major-
ity of subjects reported stereotyped episodes and in
over three-quarters of these subjects the episodes had
begun after the age of 50. Well over half of peo-
ple who experienced such episodes reported that the
visual events occurred without headache, and the typ-
ical duration of an episode was 15–60 minutes. In con-
trast to a group of subjects who had been diagnosed
with transient ischemic attacks, patients with late-life
migraine accompaniments were far less likely to expe-
rience stroke subsequently. The authors of this study
concluded that these events were not rare, were benign,
and that “invasive diagnostic procedures or therapeu-
tic measures are generally not indicated.”
Although antiplatelet therapy such as low-dose
aspirin is sometimes used in patients with transient
ischemic attacks, there is no evidence to support its
use in patients with late-life migraine accompaniments
or other forms of aura. In the past some have advo-
cated this approach on the assumption that decreased
platelet aggregability might reduce the risk of subse-
quent ischemic events in such patients.
This practice is called into question, however, by a
recent analysis of data from the Women’s Health Study.
In subgroup analyses of this randomized trial, women
who had migraine with aura who had received 100 mg
of aspirin every other day actually had a higher risk
of subsequent myocardial infarction than women who
had not received aspirin. Although these data come
from subgroup analyses, and the risk was limited to

women who had smoked or had hypertension, they do
sound a cautionary note. In the absence of evidence
that aspirin is helpful, and some suggestion of pos-
sible harm, we do not currently recommend treating
patients with aura with aspirin therapy.
Discussion
Attacks of aura without migraine become more com-
mon as patients with migraine age. Most patients with
late-life migraine accompaniments have a prior history
of migraine and aura. In our practice we are reluctant
to make a diagnosis of aura without migraine in the
absence of a previous history consistent with migraine.
Headache expert Dr. William Young, writing about
Dr. Fisher’s masterful description of this clinically
common phenomenon, has commented that “Once
you learn of this symptom complex, you see it over and
over again. It is easy to diagnose . . . even obvious . . . No
one since has changed [Fisher’s] clinical characteri-
zation, much less improved upon it. His writing is
strange by today’s standards, with his introduction,
results section, and conclusion all mixed together, and
much of the article is composed of illustrative cases.
But once you slog through, you really will have the fla-
vor of the condition, and when you are confronted with
it, you are reassured, you reassure your patient, and
common sense rules your management.”
Diagnosis
Typical aura without headache (late-life migraine
accompaniments or “acephalgic migraine”).
Tip
Aggressive treatment or diagnostic investigation is not
warranted in patients with a clinical scenario consis-
tent with late-life migraine accompaniments. While
antiplatelet therapy such as aspirin may be helpful for
patients with transient ischemic attacks, there is no
evidence to support its use in patients with late-life
migraine accompaniments.
Prolonged aura
Case
A 36-year-old man with a 20-year history of migraine
with typical visual aura presented in the emergency
department. He reported that four hours previously
he had one of his typical auras, including scintillations
Chapter 2: Conditions that mimic primary headache
and a scotoma. After about an hour the scotoma grad-
ually faded and he developed a right-sided headache
that responded to treatment with zolmitriptan. The
scintillations, however, have continued. In the past the
visual symptoms associated with his headaches had
never lasted longer than 40 minutes. Initial neurologic
examination, including fundoscopy, was normal. The
patient was sent for urgent ophthalmologic consulta-
tion, which showed no apparent ocular disease but
did reveal an upper and lower quadrant right visual
field deficit. A CT of the head with and without con-
trast showed no abnormalities. The patient was oth-
erwise well and hematologic and chemistry tests were
normal. About six hours after onset the visual symp-
toms resolved spontaneously. An MRI scan of the head
done a month after the emergency department visit
also proved to be normal.
The patient then disappeared from care, reappear-
ing four years later. He reported that he traveled fre-
quently for his work as a consultant. He had continued
to have episodes of prolonged aura interspersed with
episodes of typical visual aura lasting no longer than
40 minutes. On several occasions he had sought eval-
uation in emergency departments in different cities,
where he had undergone several repeat CT scans, elec-
troencephalogram (EEG), and lumbar puncture with
no abnormalities found.
What is the likely diagnosis in this case?
This patient experiences aura symptoms that are com-
pletely characteristic of his typical visual aura with the
exception of their duration. Such an occurrence nat-
urally raises the suspicion of cerebral infarction, but
testing in this case does not show evidence of ischemia.
Unfortunately, the current ICHD-3 beta does not pro-
vide a diagnostic label for his episodes of prolonged
aura. The criteria for typical visual aura specify that
aura symptoms should not exceed 60 minutes. The
criteria also include the diagnosis of “persistent aura
without infarction” for cases where aura symptoms last
longer than a week in the face of normal test results.
Patients whose auras fall between 60 minutes and
a week, or who have repetitive attacks of aura with
very short intervals of normality reside in a diag-
nostic “no man’s land.” Many terms have been used
to describe this clinical situation, including “compli-
cated migraine,” “sustained visual aura,” “persistent
migraine aura,” and “migraine aura status.” Because
most patients with prolonged aura have other attacks
33
 Chapter 2: Conditions that mimic primary headache

that fulfill criteria for some other form of aura, the

authors of ICHD-3 beta recommend headaches in
those cases should be coded to that other diagnosis.
Otherwise, since they fulfill all but the duration crite-
rion for a diagnosis of typical aura, they should be clas-
sified as probable migraine with aura, specifying the
atypical feature (prolonged aura or acute-onset aura)
in parentheses.

What is the differential diagnosis of

prolonged aura?
The differential diagnosis of prolonged aura includes
vertebrobasilar transient ischemic attack, carotid or
vertebral dissection, cerebral vasculitis, reversible
cerebral vasoconstrictive syndrome, occipital lobe
epilepsy, or even cerebral venous thrombosis. In the
case of this patient, those possibilities were elimi-
nated by normal testing results. The passage of time
without the development of additional problems also
makes a dangerous explanation for his prolonged
auras unlikely. Unfortunately, this patient’s peripatetic
lifestyle meant that he was subjected to repeat diagnos-
tic testing to rule out dangerous diagnoses that might
have accounted for his presentation.
Discussion
Persistent aura symptoms are not especially common
but numerous case reports make it clear that they do
occur. Persistent visual aura is often distressing for
patients, who frequently report that they are either
unable or afraid to drive. Figure 2.6 shows a draw-
ing that illustrates visual abnormalities similar to those
depicted by a 70-year-old man who suffered from
repetitive attacks of aura for five weeks; looking at
this it is not hard to understand how disabling per-
sistent attacks of aura can be. In commenting on the
patient’s drawing, noted aura experts report that “Each
repetition began with slowly undulating thick gray
lines, which changed in a few minutes into a pinwheel
of bright whirling color in his left visual field. Sev-
eral minutes later this image slowed down and dis-
appeared. After more than a week of suffering these
hallucinations, he also developed brief attacks of ‘elec-
trical’ paresthesias in his left hand. These were less fre-
quent than the visual phenomena and alternated with
them irregularly. Throughout his ordeal, he had a dull
headache over his right eye.” Because this is a rela-
tively rare condition, there are no large clinical trials
Figure 2.6 This drawing illustrates visual abnormalities of the kind
described by a patient experiencing repeated attacks of visual aura.
After Haas. Prolonged migraine aura status. Ann Neurol. 1982;11:
197–9. From www.drpaulrizzoli.com. Used with permission.
on which to base treatment recommendations. Case
reports provide empirical support for trials of lamot-
rigine, acetazolamide, or valproic acid.
Diagnosis
Migraine with aura.
Tip
Aura symptoms that last longer than an hour but less
than a week are difficult to classify. In patients who also
have attacks of aura of typical duration, it is reasonable
to assign a diagnosis of migraine with aura.
A middle-aged woman with vertigo
and a history of migraine
Case
A 54-year-old woman was referred to the headache
clinic by her primary care physician for possible
migrainous vertigo. She had a history of migraine
without aura in her 20s, which had largely abated after
the birth of her last child in her late 30s. About three
years ago she started having episodes of vertigo, lasting
about two hours and initially occurring twice a month.
When she had the vertigo, turning her head quickly
exacerbated it. It did not seem to be provoked by any
environmental factors such as dehydration. There was
no headache associated with the vertigo, though she
did note photo and phonophobia during some of the
episodes.

34

Table 2.9. Clinical characteristics of migraine with brainstem
aura
Aura must be followed within an hour by headache
Aura must occur with at least two brainstem symptoms,
which include decreased level of consciousness, tinnitus,
vertigo, dysarthria, diplopia, hypacusis, or ataxia
Each symptom can last 5–60 minutes, at least one symptom
is unilateral, and at least one spreads gradually and/or at
least two symptoms occur in succession
She had seen an otolaryngologist. Her examina-
tion, done at a time when she was not symptomatic,
was normal. Specifically, a Dix–Hallpike maneuver did
not provoke nystagmus. An MRI of the brain was nor-
mal. She was diagnosed with benign positional parox-
ysmal vertigo and started on meclizine, which was
ineffective and made her tired. Her primary care physi-
cian thought the vertigo might be related to her history
of migraine and referred her to the headache clinic.
Could this patient’s vertigo be migrainous
in origin?
The first two versions of the ICHD did not include
criteria for migrainous vertigo or migraine-associated
vertigo. ICHD-3 beta, however, lists criteria for
vestibular migraine in the appendix, which is a place
for candidate criteria for disorders that need further
validation and testing. These criteria describe migrain-
ous vertigo as the occurrence of moderate to severe
vestibular symptoms lasting 5 minutes to 72 hours,
where at least half of the episodes are associated with
headache, visual aura, or photophobia and phonopho-
bia. These symptoms must occur in a patient who
meets diagnostic criteria for migraine.
It should also be noted that vertigo is listed as one
of the brainstem symptoms characterizing “migraine
with brainstem aura,” formerly known as basilar
or basilar-type migraine. These criteria are listed in
Table 2.9. The classification notes that while there
is some overlap between the two syndromes, most
patients with vestibular migraine experience vertigo
for longer than an hour. They also rarely experience
vertigo in the same relationship to headache that
is seen with typical migraine with aura, where the
aura immediately precedes and is usually followed by
headache. Instead, headache may not always occur
in relation to vertiginous symptoms, and may coex-
ist with rather than follow them. In addition, migraine
with brainstem aura requires typical visual aura symp-
Chapter 2: Conditions that mimic primary headache
toms in addition to those believed to originate in the
brainstem.
What treatments are available to
this patient?
Until recently, research regarding treatment for
vestibular migraine has been limited by the absence
of clear, agreed-upon diagnostic criteria. There have
been no randomized controlled trials of treatments
for vertigo linked to migraine and high quality evi-
dence to guide treatment is therefore lacking. One
small and underpowered trial suggested benefit from
zolmitriptan for acute treatment. Larger chart review
or survey studies suggest that medications prescribed
for migraine were generally effective in treatment of
the vertigo in patients with both vertigo and migraine.
Small interventional studies, typically open label, have
evaluated beta-blockers, tricyclic antidepressants, cal-
cium channel blockers, and antiepileptic drugs. One
interventional study included a dietary modification
that appeared to be beneficial for a subset of patients,
although in our view such open-label results should
be interpreted with caution.
Given the lack of a solid evidence base to guide
treatment decisions, we typically start by treating
vestibular migraine as we do any other form of
migraine, with an emphasis on prevention if attacks are
frequent. Specific preventive medications to be con-
sidered include propranolol, amitriptyline, and top-
iramate. Lifestyle modifications including adequate
and regular sleep, maintaining good hydration, and
a healthy diet are also emphasized. For treatment of
acute episodes of headache or vertigo, a trial of triptans
may be fruitful, even in patients without migrainous
headache accompanying the episodes of vertigo. Seda-
tive medications such as meclizine or benzodiazepines,
often used in the treatment of vertigo of peripheral
origin, are another option. Lastly, physical therapy or
vestibular therapy might be considered.
Discussion
Vertigo is the sensation of rotational motion when
the head and body are actually at rest. Patients often
describe the feeling that they or the room are spinning;
this sensation of movement distinguishes “vertigo”
from “dizziness.” Vertigo may occur spontaneously or
may be triggered, often by a change in head position
but also at times by visual triggers. Any of these types
35
 Chapter 2: Conditions that mimic primary headache
of vertigo may be accompanied by migrainous symp-
toms, whether headache or sensitivity to other sen-
sory modalities, to suggest a diagnosis of vestibular
migraine.
There is a wide variation in the duration of vertigi-
nous symptoms, from minutes to days. The pathophys-
iology of vestibular migraine is not well understood,
but an overlap between vestibular input and circuits
involved in migraine seems likely. Both clinical and
research interest in the topic has increase significantly
over the last several years. The ICHD-3 beta notes
that the temporal course of vestibular migraine rarely
fits the pattern for typical aura (duration 5–60 min-
utes, immediately preceding headache) and therefore
“episodes of vestibular migraine cannot be regarded as
migraine auras.”
Although the ICHD-3 beta has included these
diagnostic criteria in order to stimulate further
research aimed at validating the disorder, it is worth
noting that other criteria for the diagnosis exist.
Otolaryngologists may use the Neuhauser criteria.
A diagnosis of definite migrainous vertigo by these
criteria requires: (1) recurrent vestibular vertigo; (2)
migraine according to the International Headache
Society (IHS); (3) migrainous symptoms during at
least two vertiginous attacks (migrainous headache,
photophobia, phonophobia, or aura symptoms); and
(4) vertigo not attributed to another disorder. Prob-
able migrainous vertigo requires items 1 and 4 and
another migrainous feature (migraine per IHS crite-
ria, migrainous symptoms during vertigo, migraine
triggers for vertigo, response to anti-migraine
drugs).
Chronification of vertiginous symptoms is not as
well described in the literature, but anecdotally we
have occasionally seen patients evolve from episodic to
chronic vertigo, seemingly in a process like that which
occurs with headache. The symptoms may become less
severe but more frequent or continuous over time,
a phenomenon commonly seen with other migraine-
associated symptoms such as photophobia. When the
vertigo is not accompanied by headache or is not tem-
porally associated with headache it is often unclear
whether the vertigo is a migrainous symptom. In those
cases we often empirically treat patients as if they have
chronic migraine.
Diagnosis
Vestibular migraine.
36
Tip
A diagnosis of vestibular migraine may be considered
for patients with a history of migraine when the ver-
tigo is associated with other migrainous symptoms and
other etiologies have been ruled out.
Further reading
Sinus disease
Eross E, Dodick D, Eross M. The Sinus, Allergy and
Migraine Study (SAMS). Headache. 2007;47(2):213–24.
Schreiber CP, Hutchinson S, Webster CJ, et al. Prevalence
of migraine in patients with a history of self-reported or
physician-diagnosed “sinus” headache. Arch Intern Med.
2004;164(16):1769–72.
Lyme disease
Halperin JJ, Shapiro ED, Logigian E, et al. Practice
parameter: treatment of nervous system Lyme disease
(an evidence-based review): report of the Quality
Standards Subcommittee of the American Academy of
Neurology. Neurology. 2007;69(1):91–102.
Nord JA, Karter D. Lyme disease complicated by
pseudotumor cerebri. Clin Infect Dis. 2003;37(2):e25–6.
TMD
LeResche L. Epidemiology of temporomandibular
disorders: implications for the investigation of etiologic
factors. Crit Rev Oral Biol Med. 1997;8(3):291–305.
Schiffman E. Diagnostic criteria for headache attributed to
temporomandibular disorders. Cephalalgia. 2012;32(9):
683–92.
Postpartum headache
Cardona L, Klein AM. Early postpartum headache: case
discussions. Semin Neurol. 2011;31(4):385–91.
Klein AM, Loder E. Postpartum headache. Int J Obstet
Anesth. 2010;19(4):422–30.
Chiari malformation
Grazzi L, Andrasik F. Headaches and Arnold-Chiari
syndrome: when to suspect and how to investigate. Curr
Pain Headache Rep. 2012;16(4):350–3.
Massimi L, Peppucci E, Peraio S, Di Rocco C. History of
Chiari type I malformation. Neurol Sci. 2011; 32(Suppl
3):S263–5.
Mea E, Chiapparini L, Leone M, et al. Chronic daily
headache in the adults: differential diagnosis between
symptomatic Chiari I malformation and spontaneous
intracranial hypotension. Neurol Sci. 2011;32(Suppl
3):S291–4.

Pascual J, González-Mandly A, Martı́n R, Oterino A.
Headaches precipitated by cough, prolonged exercise or
sexual activity: a prospective etiological and clinical
study. J Headache Pain. 2008;9(5):259–66.
Taylor FR, Larkins MV. Headache and Chiari I
malformation: clinical presentation, diagnosis, and
controversies in management. Curr Pain Headache Rep.
2002;6(4):331–7.
Cluster presenting as a dental problem
Bahra A, Goadsby PJ. Diagnostic delays and
mis-management in cluster headache. Acta Neurol
Scand. 2004;109(3):175–9.
Balasubramaniam R, Klasser GD. Trigeminal autonomic
cephalalgias. Part 1: cluster headache. Oral Surg Oral
Med Oral Pathol Oral Radiol Endod. 2007;104(3):
345–58.
Bittar G, Graff-Radford SB. A retrospective study of
patients with cluster headaches. Oral Surg Oral Med Oral
Pathol. 1992;73(5):519–25.
Gross SG. Dental presentations of cluster headaches. Curr
Pain Headache Rep. 2006;10(2):126–9.
Rozen TD, Fishman RS. Female cluster headache in the
United States of America: what are the gender
differences? Results from the United States Cluster
Headache Survey. J Neurol Sci. 2012;317(1–2):17–28.
Shoji Y. Cluster headache following dental treatment: a case
report. J Oral Sci. 2011;53(1):125–7.
Late-life migraine accompaniments
Fisher CM. Late-life migraine accompaniments as a cause
of unexplained transient ischemic attacks. Can J Neurol
Sci. 1980;7:9–17.
Chapter 2: Conditions that mimic primary headache
Kurth T, Diener H-C, Buring JE. Migraine and
cardiovascular disease in women and the role of aspirin:
subgroup analyses in the Women’s Health Study.
Cephalalgia. 2011;31(10):1106–15.
Wijman CA, Wolf PA, Kase CS, Kelly-Hayes M, Beiser AS.
Migrainous visual accompaniments are not rare in late
life: the Framingham Study. Stroke. 1998;29(8):1539–
43.
Young WB. A knockout punch: C. Miller Fisher’s migraine
accompaniments. Headache. 2000;48:726–7.
Repetitive and prolonged migraine aura
Chen WT, Fuh JL, Lu SR, Wang SJ. Persistent migrainous
visual phenomena might be responsive to lamotrigine.
Headache. 2001;41:823–5.
Haan J, Sluis P, Sluis LH, Ferrari MD. Acetazolamide
treatment for migraine aura status. Neurology.
2000;55:1588–9. http://www.migraine-aura.org/content/
e25968/e26078/e26305/index en.html.
Haas DC. Prolonged migraine aura status. Ann Neurol.
1982;11:197–9.
Vestibular migraine
Bisdorff AR. Management of vestibular migraine. Ther Adv
Neurol Disord. 2011;4(3):183–91.
Furman JM, Marcus DA, Balaban CD. Vestibular migraine:
clinical aspects and pathophysiology. Lancet Neurol.
2013;12(7):706–15.
Lempert T, Neuhauser H, Daroff R. Vertigo as a symptom
of migraine. Ann NY Acad Sci. 2009;1164:242–51.
Neuhauser H, Leopold M, von Brevern M, Arnold G,
Lempert D. The interrelations of migraine, vertigo, and
migrainous vertigo. Neurology. 2001;56:436–41 .
37
 Chapter
Missing dangerous causes of headache
3
In most patients with dangerous underlying causes of
headache there are signs and symptoms that clearly
point to the causal disorder. Typical features that sug-
gest a dangerous or secondary cause of headache
include fever, altered consciousness, or abnormal neu-
rologic findings. One example of a rarely missed diag-
nosis is temporal arteritis presenting as a classic case
of new-onset headache in an elderly person, accompa-
nied by anemia, jaw claudication, and visible tortuosity
of the temporal artery.
When such symptoms or signs are subtle or absent,
however, dangerous causes of headache can be missed
or mistakenly attributed to other disorders. Headache
is also a common symptom of many illnesses. Patients
may have more than one condition known to be asso-
ciated with headache, making it difficult to assess
causation.
Finally, a number of disorders can produce
headaches that superficially resemble nondangerous
causes of headache such as migraine or tension-type
headache. Both of these headache types are com-
mon, so many patients presenting for evaluation of
headache will have a prior history consistent with
one of these benign headache syndromes. Migraine,
for example, is a highly prevalent cause of severe
headache, with a cumulative lifetime incidence of 44%
in women and 18% in men.
A prior history of migraine or tension-type
headache in a patient with a new or different form
of headache is not necessarily reassuring, however. In
fact, patients with a well-established history of benign
headaches may be at especially high risk of having a
dangerous cause of headache mistakenly attributed to
their prior nondangerous headache disorder.
Cases in this chapter illustrate situations in which
underlying medical or structural abnormalities
responsible for headache were not recognized, and
headache was mistakenly attributed to a nondanger-
ous headache or other disorder.
38
New headache in an elderly woman
Case
A 75-year-old woman with no personal or family his-
tory of prior headache was referred to the headache
center for consultation. She reported headaches over
the last two months. The headaches began gradually
but increased rapidly to the point where they were
daily and constant. They were located over the top of
her head and radiated to her forehead and face. The
pain was variable: sometimes dull and sometimes a
pressure sensation “like my head is going to fly off.”
The pain had been especially intense over the last two
weeks. It ranged from 4 to 6 on a 0–10 pain scale. When
asked, the patient said the headaches were associated
with photo and phonophobia but she did not have nau-
sea, vomiting, or worsening of headaches with physical
activity or change of position.
The patient denied jaw claudication, visual dis-
turbances, or associated autonomic symptoms. She
reported that her sinuses felt “congested” and the
headache temporarily improved when she sneezed.
She was treating her headaches with over-the-counter
acetaminophen plus phenylephrine. She had a 15
pound weight loss over the last year and reported
that she has been told she is anemic. She was recently
seen in the emergency department because of a severe
headache, where a neurologic examination was nor-
mal and a CT scan of the head did not reveal any
explanation for her headaches. At that visit, her systolic
blood pressure ranged from 160 to 180 mm Hg. A diag-
nosis of headache due to poorly controlled hyperten-
sion was made and her blood pressure medication was
adjusted.
A sinus CT was obtained on an outpatient basis
when headaches did not improve despite better con-
trol of her blood pressure. The report she brought with
her read as follows:

IMPRESSION:
1. Multifocal sinus disease, involving the bilateral
anterior/posterior ethmoid air cells, sphenoid
sinus, and left frontal sinus. This could account for
the patient’s headache.
2. No acute intracranial abnormality.
She was started last week on amoxicillin/clavulanic
acid twice daily but her headaches continued.
What are the leading diagnostic possibilities
and how would you proceed in evaluating
them?
New-onset headache in an elderly person is a “red flag”
situation that should prompt a careful search for an
underlying causative condition. While hypertension
or sinusitis may seem like plausible explanations for
her problem, they do not entirely explain other worri-
some features such as weight loss or anemia. Giant cell
arteritis is an additional possibility that must be seri-
ously considered in any patient over the age of 50 who
presents with a new headache.
After consultation at the headache center, this
patient had blood work and additional imaging per-
formed. Results included a hematocrit of 30, an ery-
throcyte sedimentation rate (ESR) of 94 (normal 1–
20), and a C-reactive protein (CRP) of 34.6 (normal
0–5). A magnetic resonance angiogram showed nor-
mal cerebral vessels and extensive mucosal thicken-
ing of the sphenoid sinus and ethmoid air cells with
moderate mucosal thickening of the frontal sinus. The
patient was continued on amoxicillin and clavulanic
acid twice daily and 60 mg of prednisone was added
each morning; a temporal artery biopsy was also per-
formed. The patient’s headaches resolved within two
days and the temporal artery biopsy was positive for
giant cell arteritis.
Why was the correct diagnosis delayed?
Somewhat surprisingly, this elderly patient had been
seen by her primary care physician and in the emer-
gency department with complaints of new headache
but had not had either an ESR or CRP checked.
Instead, her headaches were attributed to elevated
blood pressure and later a possible sinus infection.
In hindsight, it seems clear that after these initial
diagnoses were considered, the clinicians involved did
not reflect on alternative causes for the patient’s symp-
Chapter 3: Missing dangerous causes of headache
toms, a cognitive error known as premature closure.
In one series of diagnostic errors, premature closure –
failure to consider other diagnostic possibilities once a
diagnosis had been identified that “fit the facts” – was
the most common cause of missed diagnoses.
In this case the initial diagnoses only partially “fit
the facts.” Although the patient’s blood pressure was
indeed high in the emergency department, there were
no other signs or symptoms consistent with a diag-
nosis of hypertensive encephalopathy. This makes it
unlikely that her elevated blood pressure had occurred
abruptly, which is the only setting in which hyperten-
sion is well validated as a cause of headache. Chronic
hypertension is not commonly considered a cause of
headache. Additionally, this patient’s headaches did
not improve even with better control of her blood
pressure.
The CT scan shows extensive sinus disease, which
might account for the patient’s headaches – indeed, the
radiology report suggests so – but antibiotic treatment
did not produce improvement in her symptoms. Some
sinus infections respond poorly to antibiotics, how-
ever, so sinusitis may in fact be contributing to this
patient’s symptoms, but it is far from being the only
possible explanation. Diagnostic delay is not uncom-
mon in giant cell arteritis. Predictably, delayed diag-
nosis is more common in patients like this one who do
not present with “typical” features such as jaw claudi-
cation or visual disturbance.
Visual loss is the most feared complication of giant
cell arteritis. Visual symptoms in combination with
new-onset headaches would prompt most clinicians
to consider a diagnosis of giant cell arteritis. How-
ever, visual problems are found in only a quarter to a
third of patients at presentation. This patient did have
headache, which is the most common initial symptom,
found in almost 90% of patients. Unfortunately, this
symptom alone was not enough to prompt consider-
ation of giant cell arteritis in the presence of attractive
competing explanations.
Discussion
The gold standard for diagnosis of giant cell arteritis
is temporal artery biopsy. Most patients will also have
elevated inflammatory markers. CRP may be more
sensitive than the ESR, but either can be normal in
the occasional patient with documented disease. Thus,
most clinicians order both tests to improve diagnostic
sensitivity.
39
 Chapter 3: Missing dangerous causes of headache
The clinical presentation of giant cell arteritis is
highly variable, and this can make diagnosis difficult.
As was done in this case, steroid treatment should
be initiated immediately if clinical suspicion of giant
cell arteritis is high. Most experts agree that a few
days of steroid treatment will not reduce the likelihood
of a positive biopsy result. A normal temporal artery
biopsy does not rule out a diagnosis of giant cell arteri-
tis; false-negative biopsies can occur if unaffected por-
tions of the artery (so-called “skip lesions”) are sam-
pled in the biopsy. In this patient’s case, a high clinical
index of suspicion for giant cell arteritis was present
and the clinicians involved agreed that they would
proceed with steroid treatment even if the biopsy
were normal. She may well have coexistent sinus dis-
ease, too, and her clinicians planned to consult an
otolaryngologist.
Diagnosis
Giant cell arteritis.
Tip
Many elderly patients have a large number of medical
conditions that might plausibly cause or contribute to
new-onset headaches. It is important to consider fully
all possible explanations for headache rather than pre-
maturely settling on the first diagnosis that appears to
fit the facts of the case.
A young man with head pain, nausea,
and fever
Case
A healthy 22-year-old man was seen in the emer-
gency department for new-onset headaches. He was
well until two weeks ago, when he began to experience
intermittent severe left eye pain and head and face pain
associated with fever, chills, nausea, and vomiting. The
pain worsened with coughing, sneezing, or physical
exertion. The headache was located over the vertex
and occiput and the face pain in the V1 distribution.
There was a history of an upper respiratory infection
a week before onset of the headaches, but at the time
of presentation the patient had no nasal or respira-
tory symptoms. Physical and neurologic examination
revealed no abnormalities other than a slightly ele-
vated temperature of 101 degrees Fahrenheit. A diag-
nosis of new-onset migraine was made and the patient
40
was treated with intravenous promethazine, with some
symptomatic improvement.
Does this sound like migraine?
While some features of the patient’s headaches are con-
sistent with a diagnosis of migraine, other things, such
as the fever and chills, are not. The headaches are of
new onset and his pain is side-locked. All of these
things suggest that further evaluation is warranted. In
this case, a CT scan of the brain was ordered by the
emergency department and performed as soon as the
patient’s pain had improved with treatment. The films
showed an air/fluid level in the left sphenoid sinus.
Laboratory tests done in the emergency department
showed an elevated CRP of 12 and an ESR of 32.
In view of his new-onset headaches and his-
tory of fever and elevated inflammatory markers, the
patient also has a lumbar puncture and is sent for
blood cultures, and oral antibiotics are started. The
cerebrospinal fluid (CSF) is clear, the opening pres-
sure normal, and there is no pathogen growth at 48
hours. Blood cultures, however, grow Haemophilus
influenzae.
What is the next step in management?
The positive blood cultures confirmed septicemia. The
source of the infection was most likely the left sphe-
noid sinus, given the patient’s prominent eye, head,
and face pain and sinus abnormalities on CT scan.
A careful search for sources of head and neck infec-
tion should start with a detailed ear, nose, and throat
examination. In this case, an otolaryngologist noted
pus in the left superior turbinate and confirmed the
clinical impression of acute sphenoid sinusitis. The
patient was treated with high-dose antibiotics and sur-
gical debridement of the sphenoid sinus and recovered
uneventfully.
Acute sphenoid sinusitis is not a common con-
dition. It can be difficult to diagnose since typical
signs and symptoms of sinusitis often are not present.
For example, nasal congestion, discharge, or postnasal
drips are not common in sphenoid sinusitis, which
instead tends to present with headache and fever. The
pain may be felt over the vertex, occiput, or in the peri-
orbital region, and nausea is common. Pain is often
worsened by coughing or physical exertion. It is easy
to see how such a presentation could be mistaken for
migraine, as it was in this case. Fortunately, however,
diagnostic workup for secondary causes of headache

Table 3.1. Structures adjacent to the sphenoid sinus that may
be affected by sphenoid disease
Cranial nerve 2
Cranial nerve 3
Cranial nerve 4
First division of cranial nerve 5
Second division of cranial nerve 5
Cranial nerve 6
Dura mater
Pituitary
Cavernous sinus
Internal carotid artery
Sphenopalatine ganglion
Sphenopalatine artery
Pterygoid canal and nerve
was pursued even after the preliminary diagnosis of
migraine had been made.
Acute sphenoid sinusitis can be very serious,
so aggressive treatment is warranted. The sphenoid
sinuses lie within the sphenoid bone in the mid-
dle cranial fossa, adjacent to many critical structures
(Table 3.1). These include the pituitary and the cav-
ernous sinus. If infection spreads to the cavernous
sinus or subarachnoid space, life-threatening com-
plications can develop. The most common causative
organisms are bacterial, especially staphylococcal or
streptococcal infections, but fungal infections or
Gram-negative infections can also occur.
What is the nociceptive innervation of
the paranasal sinuses?
Sensation from the nasal mucosa and sinuses is trans-
mitted through the first and second divisions of the
trigeminal nerve with a very small contribution from
the greater superficial petrosal branch of the facial
nerve. In particular, the sphenoid and ethmoid sinuses
are served by the posterior ethmoidal branch of the
nasociliary nerve, which arises from the first divi-
sion of the trigeminal nerve. This may account for
the prominent occurrence of orbital and peri-orbital
pain in cases of sphenoid sinusitis, since pain from
the sinuses is usually referred to the corresponding
dermatome.
In contrast, the maxillary sinus is innervated by
the superior alveolar and infraorbital branches of the
Chapter 3: Missing dangerous causes of headache
second division of the trigeminal nerve, so mid-facial
pain is more common with maxillary sinusitis. The
frontal sinuses are innervated by the supraorbital
and supratrochlear nerves of the first division of the
trigeminal nerve.
Discussion
Some forms of sinusitis can be serious. This is espe-
cially true of sphenoid sinusitis. Untreated, infection
can spread to involve the cavernous sinus or cause
meningitis. Headache is the most common present-
ing symptom, and several case series suggest that the
headache often awakens patients from sleep. Sphenoid
sinusitis is also on the list of disorders that can produce
sudden onset of extremely severe headache – so-called
“thunderclap” headache – perhaps as a result of exten-
sion of infection through the wall of the sinus.
The location of the headache is variable: it is often
over the vertex in addition to causing pain in the face or
over the sinus region. Sensory changes in V1 or V2 or
pus in the middle or superior turbinates on examina-
tion can help make the diagnosis, but these findings are
not always present. X-rays or CT may show opacifica-
tion of the sinus or thickening of the mucosa, but there
is no clear correlation between the extent of opacifica-
tion and the severity of illness. CT is probably some-
what better than MRI for the diagnosis of sinusitis, but
either is probably sufficient for initial evaluation. In a
review of 300 CT and MRI scans, the sphenoid sinus
was visualized in all of the studies.
Diagnosis
Acute sphenoid sinusitis.
Tip
Acute sphenoid sinusitis can be missed when it mim-
ics migraine by producing peri-orbital pain and nau-
sea. It should be considered in any case of new-onset
headache, particularly in the presence of fever or signs
of inflammation with pain over the vertex of the head.
Weekend headache
Case
A 23-year-old woman had been seen multiple times
over the last six months for complaints of headache.
She had no prior history of headache although an
aunt had migraine. She described the headaches as
41
 Chapter 3: Missing dangerous causes of headache
constant. When headaches began they mostly oc-
curred on weekends or holidays but quickly became
daily. Typically they were worst in the mornings and
continued to be more severe on weekends. The pain
was described as throbbing, and was rated on average
6 on a scale of 0–10.
Headaches were associated with dizziness, nau-
sea, occasional vomiting, and, on two occasions,
loss of consciousness. With both episodes of loss of
consciousness she was taken to the emergency depart-
ment. Testing included an MRI scan of the head, elec-
trocardiogram, Holter monitor, and electroencephalo-
gram, all of which were normal with the exception of
occasional episodes of supraventricular tachycardia.
On both occasions she slowly improved during
a short hospitalization for observation and was dis-
charged with a diagnosis of chronic migraine. Treat-
ment aimed at migraine had not been helpful, however.
The patient reported modest, temporary relief from
anti-inflammatory medications but none at all from
triptans or a variety of preventive medications such as
propranolol and topiramate.
Based on this patient’s clinical presentation,
what are some diagnostic considerations?
The patient’s age and sex, the throbbing character of
the headache, its duration and frequency, as well as
associated features of nausea and vomiting all fit with
a diagnosis of chronic migraine. It is also the case that
many people with migraine report they are more likely
to have headaches on weekends, holidays, vacations, or
at other times of “letdown” from stress.
Other features of this patient’s headache, however,
did not fit with migraine: migraine is not typically
associated with loss of consciousness, and it is rare
for it to evolve so quickly to the chronic form of the
disorder. Could this be new daily persistent headache
which, as its name implies, presents as a constant
headache? Perhaps, but the episodes of loss of con-
sciousness still cannot be explained by that diagnosis.
In this case, the rapid evolution of the headache
after onset, the unexplained episodes of loss of con-
sciousness, and the lack of response to extensive tri-
als of treatment aimed at migraine suggested that
alternative diagnoses should be considered. In cases
of difficult-to-diagnose headache, most experts agree
that the crucial next step is “history, history, and more
history.”
42
Upon further questioning the patient confirmed
that she had no prior history of headache. She worked
as a technical editor and was able to do much of
her work at home. As her headaches have worsened
she had been spending more and more time at home
and remarked that “I can’t remember the last time I
was in my office . . . the worse I get the more time I
spend at home and the more time I spend at home the
worse I seem to get.” When asked about relatives with
headache problems, the patient again mentioned her
aunt. She added that she shared a house with her sis-
ter, who worked as a flight attendant. Her sister had
recently also developed low-grade headache and nau-
sea, but her headaches did not seem to be as severe.
Does the additional history change your
mind about possible diagnoses?
The patient’s offhand comment about getting worse as
she spent more time at home was a clue to her diag-
nosis, as was the history of a similar illness in some-
one who lived with her. Headaches were initially most
noticeable on weekends, when she was most often at
home. As her illness progressed, she began to spend
more time at home, at which point the headaches wors-
ened and became daily.
All of these facts are consistent with a toxic envi-
ronmental exposure in the home as a possible cause
of headache. When her physicians learned that the
patient’s headaches began last October with the onset
of cold weather they became suspicious about possible
carbon monoxide exposure. On testing, the patient’s
carboxyhemoglobin level was 28% and her sister’s was
18%. Inspection of their home showed a faulty furnace.
Carbon monoxide poisoning can be very diffi-
cult to diagnose when it results from chronic expo-
sure to carbon monoxide from defective space heaters,
kitchen stoves, or furnaces. The symptoms are non-
specific and easily attributed to other disorders such
as migraine. In this case the patient’s age, sex, and
headache features, including the weekend occur-
rence of the headaches, all fit with a diagnosis of
migraine.
Because migraine is so common in young women,
it is a diagnosis that most physicians can easily call to
mind. This is an example of a cognitive bias known
as “availability bias,” in which the differential diag-
nosis is strongly influenced by what is easily recalled.
Here it was easy to assume that the weekend headaches
reported by the patient were the typical “letdown”

headaches of migraine, and not so easy to remember
that at a more fundamental level they were related to
absence from work – and exposure to the home envi-
ronment – factors that might have reminded her doc-
tors about environmental exposures that can produce
headache.
Discussion
Carbon monoxide is odorless, so victims are not aware
of exposure. It binds more tightly to hemoglobin than
oxygen, with the result that oxygen delivery to the
brain and other tissues is impaired. Diagnosis is based
on finding a venous carboxyhemoglobin level above
10%.
Headache is the most common symptom of car-
bon monoxide poisoning and is thought to result
from cerebral vasodilation in response to hypoxemia.
Nausea and a general sense of malaise or other flu-
like symptoms are also common. The higher the car-
boxyhemoglobin level and the more sustained the
exposure, the worse the long-term outcome. Chronic
encephalopathy can result with prolonged or very high
level exposure.
Carbon monoxide poisoning is treated by removal
from the exposure and with oxygen therapy; 100%
oxygen is commonly administered for several hours.
If carboxyhemoglobin levels are above 25%, guide-
lines recommend the use of hyperbaric oxygen at
2–3 atmospheres, if available. Hyperbaric oxygen
rapidly increases the amount of oxygen that is dis-
solved in plasma and the half-life of carboxyhe-
moglobin is shortened from 4–5 hours in room air to
about 20–25 minutes. There can be complications to
hyperbaric treatment, including tension pneumotho-
rax or cerebral edema. It is contraindicated in patients
with chronic obstructive pulmonary disease.
One study found that roughly 15% of patients with
headache who presented during the winter months to
an urban emergency department had elevated carbon
monoxide levels. Another study found that smoking a
high number of cigarettes daily, use of a stove to heat
living spaces, and similar illness in a family member
were predictive of carbon monoxide poisoning, under-
scoring the value of a good environmental exposure
history.
Diagnosis
Carbon monoxide intoxication.
Chapter 3: Missing dangerous causes of headache
Tip
Weekend headaches are a hallmark of migraine, but
not all weekend headaches are migraine. Occult car-
bon monoxide poisoning can produce headache that is
difficult to distinguish from migraine. In patients with
refractory headaches occurring in winter and with
similarly affected cohabitants, a high index of suspi-
cion for carbon monoxide poisoning is appropriate.
A young woman with seizure
and headache
Case
A 19-year-old woman with epilepsy was referred to
the headache clinic for management of very severe
headaches occurring after seizures. She was diagnosed
with complex partial seizures two years ago and was
undergoing treatment trials with antiepileptic drugs.
Her seizures were less frequent with topiramate but
still occurred about once every other month.
Following her seizures she experienced unilateral,
throbbing, severe headache with photophobia, nausea,
and vomiting. She rated the headaches as “10+” on
a 0–10 pain scale and reported they could last up to
a whole day. The pain was not relieved by ibuprofen.
Because she and her epileptologist were primarily con-
cerned about controlling seizures, the headaches had
not been a focus of attention until recently.
Upon further questioning she admitted having
occasional milder but similar headaches outside of
the seizure episodes, often around her menstrual
period. Her mother had “sick headaches” when she was
younger.
What is the relationship between seizures
and headaches?
The International Classification of Headache Disor-
ders (ICHD) recognizes two forms of headache asso-
ciated with epileptic seizures. The first, hemicrania
epileptica, is diagnosed when headache is a primary
manifestation of the seizure itself. The diagnostic cri-
teria include headache lasting seconds to minutes,
with features of migraine, developing synchronously
with a partial epileptic seizure and resolving imme-
diately after the seizure. The pain must be ipsilateral
to the ictal discharge. This is a relatively uncommon
phenomenon.
43
 Chapter 3: Missing dangerous causes of headache
Much more common is post-ictal headache, which
is diagnosed when a headache occurs after a seizure.
The criteria include a headache with features of
tension-type or migraine headache, developing within
three hours after a partial or generalized epileptic
seizure and resolving within 72 hours after the seizure.
Prevalence estimates for post-ictal headache range
from 25% to 50%.
Migralepsy, a disorder in which migraine is the
putative trigger for an epileptic seizure, has been
very rarely described and is a controversial diagno-
sis. Migraine and epilepsy share many features. Both
are chronic neurologic disorders of long duration with
episodic manifestations and exacerbations. Both dis-
orders are characterized by paroxysmal “all or none”
events.
While the exact pathophysiology of migraine with-
out aura is unclear, it is generally accepted that
migraine aura is associated with excessive cortical
excitation, as is seizure activity. In migraine, cortical
hyperexcitability is theorized to lower the threshold
for cortical spreading depression, in which an orderly
wave of neuronal depolarization travels across the sur-
face of the cortex. This is followed by a period of
depressed cortical activity as the neurons struggle to
repolarize. Cortical spreading depression is generally
accepted as the cause of migraine aura.
A number of similar molecular mechanisms are
theorized to play a role in at least some cases of both
disorders, such as abnormalities in ion channel func-
tion leading to increased glutamatergic tone. The pos-
sibility that migraine and epilepsy might share some
underlying mechanisms is supported by epidemiologic
evidence that shows the two disorders are comorbid.
The prevalence of epilepsy is higher in migraineurs (1–
71%) than in the general population (0.5–1%). Esti-
mates of the prevalence of migraine in the epilepsy
population range from 8.4% to 24%.
In this case, the patient has an established diagnosis
of partial complex seizures, and the temporal relation-
ship between the seizure and the resulting headaches
is clear. A diagnosis of post-ictal headache is there-
fore appropriate. Based on her history of other similar
headaches occurring in the absence of seizure, it seems
likely that she has a diagnosis of migraine as well.
What treatment options are available?
In cases where headaches occur only after seizures,
the most effective treatment is prevention of seizure
44
episodes with antiepileptic therapies. If headaches also
occur outside of seizure activity, an antiepileptic drug
with evidence of efficacy for headache may be a good
option. Antiepileptic drugs that may be effective for
both seizures and migraine include topiramate and
valproate. Evidence is less certain for gabapentin.
There is little evidence to guide the choice of
symptomatic treatments for post-ictal headache. Case
reports and clinic experience both support the prac-
tice of using migraine-specific therapies to treat
patients whose post-ictal headaches have migrainous
features. Anecdotally, some patients who have both
migraine and post-ictal headaches note that their post-
ictal headaches are more severe than their regular
migraines.
If triptans or nonsteroidal anti-inflammatory
drugs are not effective for post-ictal headache, this
may be the rare situation in which the use of butalbital-
containing drugs or opioid drugs is defensible. As
with treatment of regular migraines, antiemetic treat-
ment should be considered if nausea is a prominent
accompaniment of the headache.
The patient in this case was treated with subcu-
taneous sumatriptan and oral prochlorperazine. This
regimen was effective for most of her interictal and
post-ictal headaches. At a follow-up visit she reported
having a few very severe headaches for which this regi-
men was not effective and she was given a prescription
for a butalbital-containing medication to use in those
circumstances.
Discussion
Although epilepsy and headache may be comorbid
conditions, they can usually be distinguished on clini-
cal grounds alone. Because of this, electroencephalog-
raphy (EEG) is not useful in the initial evaluation of
patients with typical headaches. This is reflected in a
practice parameter of the Academy of Neurology. EEG
may be warranted in patients who have atypical visual
aura where conditions such as occipital lobe epilepsy
are being considered.
Headache as the sole manifestation of seizure is
very rare, while headache occurring after a seizure
with other manifestations is more typical. Post-ictal
headache is relatively common, affecting up to half of
patients with epilepsy. It may be more common in chil-
dren. Despite being common, post-ictal headache is
often overlooked. This may be because the headaches
are not very severe, or may be because the seizure is

more concerning and “overshadows” the subsequent
headache. Because these headaches may be bother-
some and refractory to minor analgesic treatments,
however, they often warrant medical attention.
Diagnosis
Post-ictal headache; episodic migraine.
Tip
Post-ictal headache is common and can be severe.
Failure to ask patients with epilepsy about post-
ictal headache, and/or failure to recognize migrainous
symptoms, may delay treatment.
Intermittent red eye and headache
Case
A 44-year-old woman reported intermittent redness
and bulging of her right eye in association with
headache. For five years, the episodes had occurred
at least once a year and lasted for up to two weeks.
During the episodes she had severe, 10/10 ipsilateral
headache without migrainous features. Toward the end
of the episodes her vision became blurry. She had been
treated with antibiotic and steroid eye drops without
benefit. Recently her symptoms had lasted longer than
usual and while she was visiting a family member in
the hospital a casual physician observer suggested she
should seek emergency evaluation.
What are the possible causes of intermittent
red eye and headache?
Redness of the eye can occur because of autonomic
dysfunction, venous congestion, or an inflammatory
condition. In this case, an inflammatory condition
such as orbital cellulitis seems unlikely given the inter-
mittent and unilateral nature of the symptoms and lack
of association with other symptoms such as fever. Cel-
lulitis is also unlikely to resolve spontanteously.
Cluster headache can present with a unilateral
red eye and ipsilateral pain, but by definition the
individual attacks cannot last for longer than three
hours. Some patients with chronic cluster headache
do develop a low-grade constant background discom-
fort in the orbital and temporal area, but the severe
nature of the pain in this case is not consistent with that
possibility.
Chapter 3: Missing dangerous causes of headache
Intermittent acute angle-closure glaucoma is
another possibility, but it does not typically last for
two weeks: the duration of a typical episode of angle-
closure glaucoma is only 30 to 60 minutes. It is usually
associated with other symptoms such as halos around
lights. This patient has reported only blurry vision.
Additionally, this patient does not report exposure
to provocative agents that are associated with the
development of acute angle-closure glaucoma, such as
a dark or dim environment, prolonged near work, or
sneezing.
Proptosis is not a feature of either cluster headache
or glaucoma. A mass lesion of the orbit or retro-orbital
area is a possibility but it is unlikely that would produce
intermittent proptosis and redness. Cavernous sinus
thrombosis could produce these symptoms, but it does
not usually remit and recur.
What is the next step in evaluation of
this patient?
The intermittent bulging and congestion of the eye
suggest the possibility of a vascular lesion and the
need for further imaging of the cerebral vessels. On
examination during an episode, this patient had right
proptosis, ptosis, and slightly decreased right visual
acuity as well as dilated episcleral vessels. The optic
discs were normal but the right retina showed some
venous engorgement. A carotid cavernous fistula was
suspected after the patient mentioned that she could
“hear my heartbeat” when the eye was bulging.
A magnetic resonance angiogram did not show
a fistula but the right cavernous sinus was enlarged.
Conventional cerebral angiography confirmed a right
carotid cavernous fistula.
Discussion
Carotid cavernous fistulas can cause eye pain, visual
loss, and proptosis, probably due to marked orbital
and cerebral venous congestion. In this case, the diag-
nosis of a carotid cavernous fistula was suggested by
the recurrent and remitting nature of the episodes in
combination with suspicious findings on examination,
particularly the ocular bruit that was audible to the
patient.
In carotid cavernous fistulas there is abnormal
communication between the carotid artery and the
cavernous sinus, usually through dural branches of the
internal or external carotid artery. These fistulas can
45
 Chapter 3: Missing dangerous causes of headache
result from trauma, but the cause of non-traumatic fis-
tulas is not known.
Elevated pressure in the cavernous sinus can pro-
duce substantial venous congestion in the orbit, with
resulting visual loss. While small fistulas may seal
over, larger and more symptomatic lesions are gener-
ally treated with endovascular techniques to close the
connection.
Diagnosis
Carotid cavernous fistula.
Tip
A red, bulging eye accompanied by headache is not
consistent with a primary headache disorder and
requires further workup.
A young woman with morning
headaches
Case
A 24-year-old female reported new-onset bilateral,
frontal, and retro-orbital headache onset every morn-
ing that resolved later in the day. There were no
associated symptoms. There was no prior history of
headache. Her neurologic examination was normal.
She was diagnosed with sinus headache and advised to
try over-the-counter decongestants.
The headaches improved but then returned about
three months later and were more intense. She
returned to her doctor, who wrote in the chart that
there were “no neurologic abnormalities.” A computed
tomographic scan of the head was ordered and she was
referred for neurologic evaluation.
Is it appropriate to order imaging in
this case?
Headache is common and usually benign, especially
when there are no associated abnormalities and the
neurologic examination is normal. If such patients
meet criteria for one of the primary headache dis-
orders such as migraine or tension-type headache,
further evaluation is unlikely to be fruitful. In these
circumstances the chance of finding a clinically mean-
ingful abnormality on neuroimaging has been esti-
mated at about 0.1%. Instead of imaging, reassurance
46
and management for the presumed benign condition
is appropriate.
In this case, though, a diagnosis of sinus headache
was made in the absence of any obvious symptoms of
sinusitis. The patient is at an age where migraine com-
monly begins, but she does not have typical features of
migraine such as nausea or sensitivity to light or noise.
Despite initial improvement, her headache problem is
progressing. Neuroimaging thus seems appropriate to
evaluate the possibility of underlying explanations for
headache.
A brain CT showed a lesion and early papilledema
was noted on funduscopic examination by the neurol-
ogist. Brain MRI showed a 4 cm enhancing lesion in
the left posterior fossa with significant mass effect on
the cerebellum and the adjacent brainstem, and partial
compression of the fourth ventricle. The patient was
admitted for further evaluation and ultimately diag-
nosed with a medulloblastoma.
This seemed like a benign headache.
What was missed?
This was a new-onset headache that did not clearly
meet criteria for any primary headache. Although the
initial visit note indicated that there were no neu-
rologic abnormalities, no funduscopic examination
was documented in the record. Thus, it is not at all
clear that the neurologic examination was normal.
Had a careful funduscopic examination been done,
papilledema might have been detected and the diag-
nosis of medulloblastoma made sooner. It also seems
likely that the initial improvement in the headache led
to a false feeling of reassurance.
Discussion
Headache is present at some point in up to 50% of brain
tumor patients, but it is rarely the presenting symptom.
Nonetheless, doctors worry about cases like this one, in
which a patient presenting with headache and no other
features turns out to have a deadly brain tumor.
The response to cases like this should not be to
image indiscriminately all patients with new-onset
headache. Even in patients with new-onset headache
the prior probability of a dangerous cause of headache
is low when there are no associated symptoms – this
particular case notwithstanding – and most imaging

findings will be “incidentalomas” that do not change
clinical care.
Rather, this case underscores the importance of a
thorough neurologic examination, including a fundus-
copic examination, in every patient with new-onset
headaches. It also illustrates the value of follow-up vis-
its and clinical monitoring. Although the underlying
tumor causing this patient’s headaches was missed at
the first visit, appropriate testing was done when she
returned to report that she was worse.
Careful monitoring of the clinical course of
headaches is a suitable way to gather more informa-
tion about a headache problem where the diagnosis is
not clear. This “watchful waiting” strategy avoids the
harms and costs that come from over-testing while
minimizing the likelihood that an important problem
will be overlooked.
Diagnosis
Medulloblastoma.
Tip
Omitting the funduscopic examination in the evalua-
tion of headache can lead to errors in diagnosis. A care-
ful examination of the optic fundi is an essential part
of the physical examination of every patient presenting
with headaches.
More morning headaches
Case
A 58-year-old obese man with a history of episodic
migraine since his teens presented for evaluation of
subacute onset chronic headache about one year ago.
The headache was holocephalic, moderate to severe in
intensity, pounding, associated with mild photophobia
and phonophobia, and worse with activity. There was
no aura. He woke up with a headache every morning
and sometimes awakened from sleep with a headache
as well. He described his sleep as broken, and said
he had been “a snorer” his whole life. His girlfriend
noticed periodic apneas over the last two years. After
nights when he didn’t sleep well, his headaches were
usually worse. A brain MRI was normal. Treatment
with multiple abortive and preventive migraine medi-
cations for a diagnosis of presumed migraine was only
Chapter 3: Missing dangerous causes of headache
of mild benefit. He was significantly limited in his daily
activities.
What are possible diagnoses for this
headache presentation and what testing
would you consider?
This patient has a history of a previous primary
headache disorder, episodic migraine, and transforma-
tion from the episodic to the chronic form of the disor-
der might be one explanation for his daily headaches.
Both snoring and sleep-disordered breathing are risk
factors for progression of migraine.
Headache that is present every morning and more
severe than at other times of day is commonly reported
in many severe chronic headache disorders. It does not
clearly point to a particular diagnosis. However, noc-
turnal hypoxia could also produce morning headache
and can be seen in association with sleep apnea syn-
drome. This seems to fit with the report of apneic
episodes during sleep.
An overnight polysomnogram in this patient
showed moderate obstructive sleep apnea. He was
started on continuous positive airway pressure therapy
(CPAP) and within one week his daily headaches had
resolved. He continued to have occasional intermittent
migraine headaches.
Discussion
Obstructive sleep apnea is often associated with
headache and is a risk factor for transformation of
migraine from episodic to chronic. All patients with
chronic headache or headache upon awakening should
be questioned about symptoms of obstructive sleep
apnea, such as frequent nighttime awakenings, wit-
nessed apneas by bed partners, unrefreshing sleep,
daytime somnolence, and irritability (Table 3.2). Cer-
tain risk factors for obstructive sleep apnea are also
easily assessed in a routine office visit, including ele-
vated body mass index (BMI), retrognathia, and pres-
ence of a large neck circumference. Some patients do
not have full apneas, but may have nocturnal hypoxic
episodes that could contribute to headache as well.
Obstructive sleep apnea and nocturnal hypoxic
episodes are evaluated with a polysomnogram, which
includes continuous oxygen saturation monitoring.
Referral to a sleep specialist or for a polysomno-
gram should be considered in any patient who reports
47
 Chapter 3: Missing dangerous causes of headache
Table 3.2. Features associated with obstructive sleep apnea
Morning headaches
Snoring
Daytime somnolence
Irritability
Unrefreshing sleep
Obesity
Large neck circumference
Poorly controlled hypertension
symptoms of obstructive sleep apnea, or has several
risk factors for obstructive sleep apnea in addition to
refractory headache. Preliminary studies suggest that
most patients with headaches and obstructive sleep
apnea have improvement of the headaches when the
disorder is effectively treated.
This patient had a known primary headache dis-
order, which might have predisposed him to hav-
ing headaches in response to another stimulus, in
this case obstructive sleep apnea. However, treatment
with migraine therapy did not completely resolve the
headache. When he received treatment for obstruc-
tive sleep apnea he reverted to his previous pattern
of episodic migraine. This illustrates the importance
of looking for other potential causes or aggravat-
ing factors of headache in patients with known pri-
mary headache disorders whose headaches change in
character.
Diagnosis
Obstructive sleep apnea causing progression from
episodic to chronic migraine.
Tip
Obstructive sleep apnea can be a cause of difficult-to-
treat chronic headaches and headaches often respond
well to treatment of apnea.
A middle-aged man with side-locked
headache
Case
A 35-year-old man had a five-year history of episodic
left-sided headache that was side-locked (i.e. did not
shift sides). The headache had been severe at times
and was difficult to control. Although there was no
48
family history of migraine or other chronic headaches
the patient was thought to have migraine. A brain
MRI scan showed a small pituitary adenoma with-
out anatomic compression or extension. The patient
reported no endocrine symptoms. The patient was
advised that the finding was very unlikely to be the
cause of his headache and additional trials of treatment
for migraine were attempted.
Three years later the patient developed severe,
chronic headache and was unable to work. A repeat
MRI showed an increase in the size of the adenoma
although there was still no evidence of extension or
compression. Careful questioning elicited symptoms
consistent with early acromegaly: an increase in shoe
and glove size and hypertrophy of the gums. After
neurosurgical evaluation he was offered surgical
removal of the adenoma through a trans-sphenoidal
approach. One month after surgery he was almost
headache-free and planning to return to work.
Should the patient initially have been
advised that the MRI finding was unrelated
to the headache pattern?
Probably not, since headache is surprisingly common
among patients with pituitary tumors. In fact, it is the
presenting feature in 40–70% of cases. It does not seem
to be related to the size of the tumor. In one small
cohort of patients who had pituitary tumors and trou-
blesome headaches, almost half had improvement in
headaches following surgery, suggesting a causal rela-
tionship. However, 15% of patients reported worsening
of headaches following surgery. Headache alone is gen-
erally not considered a sufficient indication for surgery
because of this uncertainty.
What are the characteristics of headaches in
people with pituitary tumors?
One study evaluated the phenotypic characteristics of
84 patients with pituitary adenomas. Headache was
side-locked in 88% of cases, and over half described the
pain as throbbing. In fact, the majority had headaches
with many of the features of migraine. The presence of
migrainous features was associated with a family his-
tory of migraine. Perhaps people with a genetic pre-
disposition to migraine are also more likely to develop
headache in the presence of a pituitary tumor.

Thus, in contrast to the general rule that headaches
due to brain tumors have features of tension-type
headache, headache associated with pituitary lesions
more often fits criteria for episodic or chronic
migraine.
Other headache patterns described with pitu-
itary lesions include cluster headache, SUNCT (Short-
lasting, Unilateral Neuralgiform headache attacks with
Conjunctival injection and Tearing), or primary stab-
bing headache. No specific tumor type is associated
with a specific headache type. Interestingly, only a
few pituitary headaches meet the official criteria for
intracranial neoplasm headache or pituitary hyper-
secretion headache, and thus revisions to the classifi-
cation have been proposed. Almost half of patients will
report severe disability due to headache.
Discussion
Pituitary headache may be more severe than typi-
cal migraine and when unilateral may often be side-
locked. Less commonly, pituitary headache may mimic
cluster or other more rare forms of primary headache.
Pituitary headache may also be chronic and disabling.
Growth hormone (GH)- or prolactin-secreting pitu-
itary tumors are more likely to be associated with
headache than nonsecreting tumors. The lack of asso-
ciation between headache and tumor size, volume, or
compression suggests that traction is not the most
likely mechanism of headache. The pathophysiology of
these headaches is more likely to reflect the hormonal
activity of the tumor than its physical characteristics.
Significant headache relief has been reported in
some instances after treatment with somatostatin
analogs, for example octreotide, in GH-producing
tumors, or dopamine agonists, for example cabergo-
line or bromocriptine, in prolactinomas.
Diagnosis
Headache associated with growth hormone-secreting
pituitary adenoma.
Tip
Pituitary tumors are a common incidental finding on
neuroimaging for headache, and it is difficult to deter-
mine whether they are the cause of headache. When
unilateral the headache is often side-locked, a histor-
ical feature that may indicate the headache is more
likely to be due to a non-migraine process.
Chapter 3: Missing dangerous causes of headache
Fatal migraine
Case
A 53-year-old man with a long history of migraine
with visual and dysphasic aura died following a two-
month attack of constant, severe left-sided headache.
The headache was associated with a persistent visual
defect typical of his previous visual aura, as well as
hemiplegia, and was assumed to be simply a particu-
larly long episode of his usual migraine.
Can migraine be lethal?
We are cheating a bit here, because this case is not
a patient from our practice. Rather, it was reported
almost 130 years ago by Féré, a resident of the famous
French neurologist Jean-Martin Charcot. Bousser and
Welch point to this as “the first case of lethal migrain-
ous stroke” but note that “in the absence of autopsy,
the precise cause of death is unknown.” The term “fatal
migraine” occasionally appears in the neurologic lit-
erature, usually referring to cases in which an appar-
ent attack of migraine aura persists and culminates in
death from stroke. Obviously, it is always difficult in
such cases to know whether the headache in question
was an early symptom of the stroke, or whether the
stroke was caused by the headache.
How might migraine aura lead to stroke?
The way in which an attack of migraine aura might
cause stroke is not definitely known. A leading pos-
sibility is that an infarct might be caused by cere-
bral hypoperfusion due to migraine aura. Decreases
in cerebral blood flow are known to occur in the set-
ting of aura, but typically are not sufficient to pro-
duce ischemic symptoms. Migraine with aura is a com-
mon, long duration condition, and sufferers may have
hundreds of auras over a lifetime. Yet true migrain-
ous infarction is rare. In unusual circumstances,
however – such as volume depletion or hypercoagula-
bility – perhaps the hypoperfusion that occurs during
aura is amplified and sufficient to produce a stroke.
Other theories are that migraine with aura is asso-
ciated with other stroke-causing conditions such as
patent foramen ovale or cerebral artery dissection. It is
also possible that vasoconstrictive treatments used for
individual attacks of migraine may occasionally pro-
duce stroke. Still another explanation is that migraine
is associated with the presence of vascular risk factors
49
 Chapter 3: Missing dangerous causes of headache
such as endothelial dysfunction that raise stroke risk.
Finally, the increased susceptibility to cortical spread-
ing depression that is a hallmark of the migraine-prone
brain may also act more generally to boost susceptibil-
ity to brain ischemia.
Discussion
Current diagnostic criteria in ICHD-3 beta allow a
diagnosis of “migrainous infarction” only in patients
known to have migraine with aura. The stroke must
develop during a typical aura, and imaging must show
a defect in the relevant brain location. Other expla-
nations for stroke must be excluded with a careful
workup. Several cases have been reported in which
patients met criteria for migrainous infarction but later
proved to have unusual explanations for stroke, includ-
ing cardiac myxoma and cerebral aneurysms.
Unsurprisingly, a large proportion of true migrain-
ous infarcts occur in the occipital lobe, which fits with
the fact that most auras are visual and arise from that
part of the brain. In addition to cases of true migrain-
ous infarction, there are numerous case reports of long
lasting aura symptoms that resolve without subsequent
stroke. A technique known as magnetic resonance dif-
fusion with apparent diffusion coefficient maps has
been used to distinguish between long-lasting aura and
true migrainous infarction.
For historical interest, let us close with yet another
case from the past: this patient is a 47-year-old man
with a long history of migraine with typical visual aura.
His visual auras always consist of a left scintillating sco-
toma, which develops gradually, fades away within 20
minutes, and is followed by a headache that meets cri-
teria for migraine. One day he had a typical attack of
visual aura but the visual abnormality did not resolve
and he was left with a permanent upper left quadrantic
defect. Your thoughts?
The case is that of a real person, a pathologist by
the name of Frank Mallory (attributed to Polyak and
reported by Bousser and Welch). He had migraine
without aura and at age 47 experienced a persistent
upper left quadrantic defect that arose during a typi-
cal visual aura. When he died 30 years later an autopsy
revealed a calcarine infarct.
Diagnosis
The first vignette is consistent with a diagnosis of
migrainous infarction and death, but 130 years later
50
and in the absence of autopsy results, this diagnosis of
“fatal migraine” cannot be confirmed.
Tip
True migrainous infarction is rare, and careful evalu-
ation is needed to distinguish it from other causes of
stroke or persistent aura without stroke.
Severe headache in a new mother
Case
A 28-year-old woman developed acute headache six
hours after a forceps-assisted vaginal delivery for
which she had epidural anesthesia. She had a his-
tory of episodic migraine with aura that she ordinar-
ily treated with sumatriptan. Her headaches had not
improved during pregnancy but she treated them only
with acetaminophen and bed rest.
Eight hours after delivery the patient reported a
severe bifrontal headache with nausea and blurred
vision. This was similar to her prior migraines but
much more severe. Her neurologic exam showed mild
diffuse hyperreflexia but was otherwise normal. Uri-
nalysis showed no proteinuria and her blood pressure
was 132/82 mm Hg. The patient reported that she had
been expecting a bad headache after delivery and asked
to be treated with sumatriptan.
Would you give this patient sumatriptan?
The patient is no longer pregnant so fears about unin-
tended effects on the baby are not a reason to avoid
the use of sumatriptan. Sumatriptan is also consid-
ered compatible with breast-feeding by the American
Academy of Pediatrics, so plans to nurse the baby like-
wise are not a contraindication to its use.
Headache occurs in about a third of women dur-
ing the postpartum period and is more common in
those with a prior history of migraine. In fact, in one
study of 1000 women with postpartum headache the
cause was migraine or another primary headache over
three-quarters of the time. This patient had a his-
tory of migraine and furthermore her headaches had
not improved substantially during pregnancy. This is
consistent with epidemiologic evidence that women
who have migraine with aura are less likely to expe-
rience pregnancy-related improvement of headaches
than women who do not have aura.

Figure 3.1 MRV images of cerebral venous thrombosis showing reduced flow in the right transverse sinus.
It is easy to understand how all of these things
suggested that the patient’s headache was a migraine
and that sumatriptan would be an appropriate way
to treat it. The patient was given sumatriptan but her
headache did not improve. In fact, she became increas-
ingly groggy and confused and several hours after
a second dose of sumatriptan she had a generalized
seizure.
Could this be something other than
migraine?
It no longer seems particularly likely that the patient’s
headache was due to migraine. Although a diagnosis
of migraine “fits the facts,” this seems another case in
which the cognitive error of premature closure might
have occurred. Other less common causes of headache
in the postpartum period also might “fit the facts.”
For example, preeclampsia can occur in the post-
partum period, and may be more common in patients
with a history of migraine, especially migraine with
aura. The patient’s blood pressure was higher than
might be expected in the postpartum setting, and she
had hyperreflexia on examination. Now she has had a
seizure. Could this be eclampsia?
Chapter 3: Missing dangerous causes of headache
The differential diagnosis of postpartum headache
is long, however, and several other disorders could
reasonably explain the findings in this case. Causes
of secondary postpartum headache can be divided
into vascular causes (stroke, venous sinus throm-
bosis, arterial dissection, vasculitis, reversible cere-
bral vasoconstrictive syndrome), and nonvascular
causes (preeclampsia/eclampsia, idiopathic intracra-
nial hypertension, post-dural puncture headache).
Notably, seizures occur in almost 40% of patients with
cerebral venous thrombosis, making that a top diag-
nostic possibility along with eclampsia.
The patient in this case was treated emergently
with intravenous magnesium and phenytoin, and had
an MRI, MRA, and MRV looking for vascular abnor-
malities. MRV confirmed transverse sinus thrombosis
(Figure 3.1). The patient was begun on low-molecular-
weight heparin and oral warfarin.
Discussion
The biggest risk of cerebral venous thrombosis occurs
during the third trimester of pregnancy and the month
following delivery. Headache is the most common
symptom, occurring in about 90% of cases. In one
series, roughly a third of patients had headaches
51
 Chapter 3: Missing dangerous causes of headache
with migrainous features, which underscores the chal-
lenge of distinguishing the early headaches of cerebral
venous thrombosis from those of migraine.
Headache in cerebral venous thrombosis is pre-
sumably due to increased intracranial pressure from
abrupt cerebral venous congestion. Papilledema is also
a common finding. About a third of patients with
cerebral venous thrombosis experience an intracranial
hemorrhage. Headaches can persist for some time after
cerebral venous thrombosis is treated.
Guidelines from the American Heart Association
and American Stroke Association encourage testing
for prothrombotic conditions such as factor V Lei-
den, protein S, or protein C deficiency in women who
have had cerebral venous thrombosis, and recommend
the use of low-molecular-weight heparin throughout
future pregnancies.
Acute-onset severe headaches, particularly those
associated with focal neurologic signs, are suggestive
of vascular etiologies. In this clinical scenario, even in
a patient with a history of benign headaches, extensive
workup is often warranted. In this case, it is unlikely
that the patient was directly harmed by sumatrip-
tan, but that would not be true if her headache had
been due to some other common causes of postpartum
headache, such as reversible cerebral vasoconstrictive
syndrome. The use of vasoconstrictive drugs such as
the triptans or ergots could produce stroke in those
cases.
Diagnosis
Cerebral venous thrombosis.
Tip
Although postpartum migraine is common, up to a
quarter of postpartum headaches are due to other
causes, including serious vascular problems that could
be worsened by vasoconstrictive medications. For this
reason, it is generally prudent to avoid triptans or
ergots in the treatment of early postpartum headache.
Further reading
Temporal arteritis
Ezeonyeji AN, Borg FA, Dasgupta B. Delays in recognition
and management of giant cell arteritis: results from a
retrospective audit. Clin Rheumatol. 2011;30(2):259–
62.
52
Graber ML, Franklin N, Gordon R. Diagnostic error in
internal medicine. Arch Intern Med. 2005;165(13):
1493–9.
Poole TR, Graham EM, Lucas SB. Giant cell arteritis with a
normal ESR and CRP. Eye 2003;17(1):92–3.
Sphenoid sinusitis
Digre KB, Maxner CE, Crawford S, Yuh WTC. Significance
of CT and MR findings in sphenoid sinus disease. AJNR
Am J Neuroradiol. 1989;10:603–6.
Lew D, Southwick FS, Montgomery WW, Weber AL, Baker
AS. Sphenoid sinusitis. A review of 30 cases. N Engl J
Med. 1983;309(19):1149–54.
Proetz AW. The sphenoid sinus. BMJ. 1948;2:243–5.
Carbon monoxide poisoning
Balzan MV, Agius G, Galea Debono A. Carbon monoxide
poisoning: easy to treat but difficult to recognise.
Postgrad Med J. 1996;72:470–3.
Heckerling PS. Occult carbon monoxide poisoning: a cause
of winter headache. Am J Emerg Med. 1987;5(3):201–4.
Heckerling PS, Leikin JB, Maturen A, Perkins JT. Predictors
of occult carbon monoxide poisoning in patients with
headache and dizziness. Ann Intern Med. 1987;107(2):
174–6.
Post-ictal headache
Förderreuther S, Henkel A, Noachtar S, Straube A.
Headache associated with epileptic seizures:
epidemiology and clinical characteristics. Headache.
2002;42(7):649–55.
Ito M, Nakamura F, Honma H, et al. A comparison of
post-ictal headache between patients with occipital lobe
epilepsy and temporal lobe epilepsy. Seizure. 1999;8(6):
343–6.
Jacob J, Goadsby PJ, Duncan JS. Use of sumatriptan in
post-ictal migraine headache. Neurology. 1996;47(4):
1104.
Rogawski MA. Migraine and epilepsy – shared mechanisms
within the family of episodic disorders. In: Noebels JL,
Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta
AV, editors. Jasper’s Basic Mechanisms of the Epilepsies
[Internet], 4th edition. Bethesda, MD, National Center
for Biotechnology Information (US). 2012.
Scher AI, Bigal ME, Lipton RB. Comorbidity of migraine.
Curr Opin Neurol. 2005;18(3):305–10.
Carotid cavernous fistula
Miller NR. Dural carotid-cavernous fistulas: epidemiology,
clinical presentation, and management. Neurosurg Clin
N Am. 2012;23(1):179–92.

Medulloblastoma
Ang C, Hauerstock D, Guiot MC, et al. Characteristics and
outcomes of medulloblastoma in adults. Pediatr Blood
Cancer. 2008;51(5):603–7.
Chan AW, Tarbell NJ, Black PM, et al. Adult
medulloblastoma: prognostic factors and patterns of
relapse. Neurosurgery. 2000;47(3):623–31; discussion
631–2.
Leary SE, Olson JM. The molecular classification of
medulloblastoma: driving the next generation clinical
trials. Curr Opin Pediatr. 2012;24(1):33–9.
Malheiros SM, Franco CM, Stávale JN, et al.
Medulloblastoma in adults: a series from Brazil.
J Neurooncol. 2002;60(3):247–53.
Obstructive sleep apnea
Bigal ME, Lipton RB. Modifiable risk factors for migraine
progression. Headache. 2006;46(9):1334–43.
Bigal ME, Lipton RB. What predicts the change from
episodic to chronic migraine? Curr Opin Neurol.
2009;22(3):269–76.
Neau JP, Paquereau J, Bailbe M, et al. Relationship between
sleep apnoea syndrome, snoring and headaches.
Cephalalgia. 2002;22(5):333–9.
Pituitary headache
Giustina A, Gola M, Colao A, et al. The management of the
patient with acromegaly and headache: a still open
clinical challenge. J Endocrinol Invest. 2008;31(10):
919–24.
Chapter 3: Missing dangerous causes of headache
Levy MJ, Matharu MS, Meeran K, Powell M, Goadsby PJ.
The clinical characteristics of headache in patients with
pituitary tumours. Brain. 2005;128(Pt 8):1921–30.
Melmed S, Casanueva F, Cavagnini F, et al. Consensus
statement: medical management of acromegaly. Eur J
Endocrinol. 2005;153(6):737–40.
Stroke in the setting of migraine
Bousser MG, Welch KMA. Relation between migraine and
stroke. Lancet Neurol. 2005;4:533–42.
Féré C. Note sur un cas de migraine ophtalmique à accès
répétéssuivis de mort. Rev Med (Paris). 1883;3:194–201.
Kurth T, Chabriat H, Bousser MG. Migraine and stroke: a
complex association with clinical implications. Lancet
Neurol. 2012;11:92–100.
Polyak S. The Vertebrate Visual System. Chicago, IL,
University of Chicago Press, 1957.
Cerebral venous thrombosis
Breteau G, Mounier-Vehier F, Godefroy O, et al.
Cerebral venous thrombosis 3-year clinical outcome in
55 consecutive patients. J Neurol. 2003;250:29–35.
Saposnik G, Barinagarrementeria F, Brown RD Jr., et al.; on
behalf of the American Heart Association Stroke
Council and the Council on Epidemiology and
Prevention. Diagnosis and management of cerebral
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professionals from the American Heart
Association/American Stroke Association. Stroke.
2011;42(4):1158–92.
53
 Chapter
Pitfalls in diagnostic testing: imaging and
4 lumbar puncture
Many causes of headache can be identified based on
the history and physical examination. Patients who
clearly meet criteria for a primary headache disor-
der generally do not need additional diagnostic test-
ing. In some cases, however, there is clinical suspi-
cion of a possible alternative diagnosis and testing is
needed to “rule out” a sinister cause of pain. In the
majority of these situations, clinical suspicion cen-
ters on possible structural or mechanical explanations
for headaches. For this reason, a good case can be
made that imaging tests and lumbar puncture (LP)
are the most important diagnostic tools in headache
medicine, with a correspondingly large number of
mistakes that can be made and adverse events that can
occur.
We all accept that failure to order a needed test,
misinterpreting test results, or lack of follow-up of
worrisome test results can lead to avoidable harm. We
are less accustomed to thinking about the possibility of
harm from ordering unnecessary tests, or other test-
related harms that are more difficult to quantify. These
include the iatrogenic anxiety that can be produced
by false-positive test results and the long-term health
risks of testing, such as the risk of cancer from test-
related radiation.
This chapter reviews cases in which imaging tests
or LP were overused, underused, or misused, as well as
situations in which complications occurred as a result
of testing. A common thread in all of these cases is
that the decision to order a test and the interpreta-
tion of test results must be considered in the con-
text of the individual patient and the specific clini-
cal situation. Test results that do not fit the clinical
picture should prompt careful reevaluation of the
situation. Recognition of adverse events from test-
ing and the appropriate management of test-related
complications are also important aspects of headache
management.
54
Refractory migraine in the emergency
department
Case
A primary care physician received a nighttime call
from an emergency department physician about a
patient of hers, a 20-year-old woman, who had inter-
mittent severe headaches. These occurred on average
twice a month and met criteria for migraine. They typi-
cally responded well to oral sumatriptan. On occasion,
though, the patient awakened with a well-established
headache and prominent vomiting and was unable to
keep her oral medications down. She then sought treat-
ment in the emergency department, as she had this
time.
Her records showed a total of six emergency
department visits over the last three years for simi-
lar headaches. The emergency department physician
reported that the patient’s neurologic examination was
normal, and the results of past testing, including three
CT scans of the head, one MRI study, and an LP, had
been normal.
What additional testing is needed?
The answer is “none.” Severe, poorly controlled pain
is a medical emergency and an appropriate reason to
seek emergency care. Nothing about this patient’s situ-
ation, however, suggests a dangerous underlying cause
of headache or points to the need for additional test-
ing. This patient meets criteria for migraine. She has
had previous emergency department visits for similar
headaches. Vomiting is a common accompaniment of
her headaches, and her consequent inability to keep
down oral medication is the main reason she is seeking
care now.

It is unlikely that another CT scan of the head
or other testing will identify anything that will alter
her management. Furthermore, the radiation risks of
diagnostic imaging are not negligible. They are highly
dependent on age, with younger people being at higher
risk than adults. The authors of a recent review of
the risks of diagnostic CT scans concluded that “In
summary, there is direct evidence from epidemiologic
studies that the organ doses corresponding to a com-
mon CT study . . . result in an increased risk of cancer.
The evidence is reasonably convincing for adults and
very convincing for children.”
A more reasonable plan would be to forgo addi-
tional diagnostic testing and treat the patient with
subcutaneous sumatriptan. If this is effective and well
tolerated, she could be given a prescription for a suma-
triptan auto-injector so that she can give herself subcu-
taneous injections of the medication when oral treat-
ment is not possible. As we mention elsewhere in
this book, patients who have a history of prominent
vomiting in association with migraine often benefit
from having such a non-oral “rescue” treatment option
available.
Can the radiation risks of a single head CT be
quantified?
Yes. Radiation doses are measured in units of ioniz-
ing energy absorbed per unit of body mass. The radi-
ation dose varies depending upon the type of imag-
ing procedure, the number of scans obtained during
the procedure, the equipment used, and other factors.
Radiation doses from CT scans are much greater than
doses from conventional X-rays. The estimated radi-
ation dose from a typical CT scan of the head, for
example, is 340 millisieverts. The radiation dose from
a single CT scan of the head may seem small, but
there is good research evidence that even exposures
in this range are associated with a statistically signif-
icant increase in the lifetime risk of cancer. These risk
estimates have not been extrapolated from studies of
higher-dose exposures, but are instead based on long-
term follow-up of groups with similar exposures. The
estimated lifetime attributable risk of subsequent brain
cancer as a result of a single CT scan of the head at age
20, for example, has been estimated at roughly 0.01%.
At age ten, the risk is 0.02%. For an individual patient
the risks are low, but on a population level it is esti-
mated that diagnostic radiation exposure may account
for 1.5–2% of all cancers.
Chapter 4: Imaging and lumbar puncture
Discussion
It is not uncommon to encounter patients with
headache who have had multiple imaging procedures,
including many that involve exposure to ionizing
radiation. Repeated, probably unnecessary, scans are
ordered when physicians and patients are frustrated
about a lack of response to treatment and fear some-
thing might have been missed. In other cases, the
results of previous scans may not be easily available,
with the result that physicians are unaware of previous
testing. The risk of unneeded testing may be especially
high in the emergency department since physicians are
often unfamiliar with the patient and fear missing seri-
ous causes of headache. In ordering diagnostic tests,
though, the possible adverse effects of testing must be
weighed against the likely benefits to the patient. In
this case, the balance of benefit to harm for any addi-
tional testing is not favorable.
Diagnosis
Migraine.
Tip
The potential adverse health effects of radiation expo-
sure should be taken into consideration when ordering
diagnostic testing for headache.
A young woman with stable headaches
Case
A 22-year-old woman sought treatment for twice-
monthly headaches that began four years ago. Her
most severe headaches were throbbing, located behind
the right or left temple, and associated with nausea
and photophobia. They typically responded to treat-
ment with an over-the-counter combination medica-
tion that contained acetaminophen, aspirin, and caf-
feine. Occasionally treatment was ineffective and she
missed a day of work. Her neurologic examination,
including funduscopic examination, was normal and
she had no other medical problems and was taking no
medications except for headache.
A friend of hers had similar headaches that
respond well to almotriptan. The patient requested a
prescription for that medication. She also requested
an MRI scan of her head, saying “I don’t think my
headaches are caused by something serious, but you
never know. I would feel better if I had a normal scan.”
55
 Chapter 4: Imaging and lumbar puncture
The physician diagnosed migraine, ordered an MRI
scan, and prescribed almotriptan.
A month later the patient returned for a follow-
up visit to review her MRI results. She reported that
almotriptan had worked well for the only headache she
had since her last visit. The MRI shows no mass lesion
or other abnormalities but the radiologist’s report
described a small arachnoid cyst in the posterior fossa.
Despite an explanation that this finding was unlikely to
be related to her headaches, the patient was not reas-
sured. She later called to request referral to a neuro-
surgeon and to obtain a copy of her scan for a second
opinion.
Were there medical reasons to scan
this patient?
The patient in this vignette met diagnostic criteria
for migraine. Her condition had been stable for sev-
eral years. A practice parameter from the American
Academy of Neurology discourages the use of diag-
nostic imaging or other testing in these circumstances.
This is because the prevalence of meaningful abnor-
malities in this clinical situation is low, on the order
of approximately 0.2%, with an upper 95% confidence
limit of approximately 0.6%. It is difficult to argue that
a brain scan was medically necessary in this patient.
Most clinicians have been faced with patients like this
one who do not have a medical reason for testing but
who request it nonetheless in order to allay anxiety.
Does testing reassure patients?
Only one study has examined this question in patients
with headache. In that study the investigators mea-
sured baseline depression and health anxiety levels in
patients with chronic daily headache and then ran-
domized them to receive or not receive an MRI scan
of the head. The results showed that patients who
received a scan were less worried about their health at
three months compared to those who had not received
a scan. By a year, however, there were no differences
in anxiety between the two groups. The group that
had received a scan, though, had lower overall medi-
cal costs than the group that had not been scanned.
All of the patients in that study had normal test
results, however, so the findings do not apply to sit-
uations like this one, in which patients undergo test-
ing and are found to have so-called “incidentalomas”
56
– that is, test results showing abnormalities that are
unlikely to be clinically significant.
Although this study suggested short-lived reduc-
tions in anxiety in patients with chronic daily headache
who underwent testing, similar studies in other con-
ditions have not clearly shown that testing reassures
patients. In a systematic review of five controlled tri-
als in a variety of conditions, four of five studies did
not find that patients were reassured. The authors con-
cluded that “the results point in the direction of diag-
nostic tests making hardly any contribution to the level
of reassurance.” They suggested that “a clear explana-
tion and watchful waiting” might make testing unnec-
essary and commented that “if diagnostic tests are
used, it is important to provide adequate pre-test infor-
mation about normal test results.”
When diagnostic imaging is indicated,
should patients be warned of the possibility
of incidental findings?
Discussing possible testing outcomes with the patient
before test results come back may be advisable. This
is because patients may have well-established beliefs
about the seriousness of their symptoms that make it
difficult for them to believe and be reassured by normal
or clinically irrelevant test results. The authors of one
study suggested that “providing an explanation about
the meaning of normal test results before testing may
weaken patients’ preconceived ideas about their ill-
ness and provide a context to help patients make sense
of the test result.” The authors tested this hypothesis
in a randomized trial among patients with chest pain
referred for a stress test. Patients who participated in a
discussion of what it would mean if they had normal
test results were more likely to report feeling reassured
at one and three months, and fewer were taking cardiac
drugs at one month.
Based on this evidence, in our practice we make a
point of discussing possible test results with patients
before we send them for testing. This includes a discus-
sion of the possibility that small abnormalities may be
identified that do not have any diagnostic or treatment
implications.
Discussion
Many doctors feel that patients will not be reas-
sured about the benign nature of their condition with-
out proof from testing that nothing is wrong. It is

not uncommon for physicians to acquiesce to patient
requests for tests that may not be necessary. Despite
their good intentions testing can cause unintended
adverse effects, including a paradoxical increase in
anxiety when results deviate from normality. Order-
ing a test may reinforce the patient’s belief that some-
thing is wrong. Some tests involve exposure to radi-
ation, which may increase the risk of later cancers.
Test results of uncertain significance may set in motion
yet more diagnostic testing or lead to treatment that
causes harm, a situation known as the “medical cas-
cade.” Unnecessary testing contributes importantly to
healthcare costs. It is also possible that patients will
continue to feel anxious and worried even after they
receive normal test results.
Diagnosis
Migraine.
Tip
There is limited evidence to support the view that diag-
nostic testing reassures patients who are anxious about
the cause of their headaches. It may be difficult to reas-
sure patients whose test results reveal minor abnor-
malities of no clinical relevance.
A young man with constant
headaches
Case
A 19-year-old man sought medical treatment for
constant, low-grade headaches with superimposed
episodes of more severe headache several times a week.
He reported a history of carsickness and intermit-
tent headaches dating back to childhood. Many mem-
bers of his family, including his mother and a sis-
ter, had severe episodic headaches and had been diag-
nosed with migraine. When he was a child the patient’s
headaches occurred on average twice a month, but
about a year ago they had gradually worsened and
become constant. Severe exacerbations of headache
were described as global; throbbing; and associated
with photo and phonophobia, nausea, and vomit-
ing. These episodes of more severe headaches seemed
to be brought on by emotional stress and had been
responsive to both triptans and nonsteroidal anti-
inflammatory medications such as aspirin. The patient
was not experiencing difficulties in school or daily
Chapter 4: Imaging and lumbar puncture
activities as a result of the headaches and was able to
exercise if the headaches were low grade.
A complete review of systems was negative and
the patient had no prior history of medical problems.
His general and neurologic examinations were nor-
mal. The physician did not believe that further diag-
nostic testing was indicated. The patient was advised
to begin a low dose of amitriptyline as a preventive
medication and continue using a triptan to treat severe
headaches.
Were there medical reasons to scan
this patient?
This young man’s headaches met diagnostic criteria
for chronic migraine. He had experienced a change in
headache pattern – something that might be consid-
ered a “red flag” historical feature – but the transfor-
mation from episodic to chronic headache occurred
a year ago and was gradual. Furthermore, his neuro-
logic examination was normal. Additional reassuring
historical features are the strong family and personal
history of migraine and the carsickness, which is often
viewed as a childhood precursor of migraine.
Patients like this are familiar to anyone who works
in a specialty headache clinic; in fact, this clinical pat-
tern of early childhood onset of migraine headaches
with the gradual development of daily or near-daily
headache is an extremely common clinical scenario.
There is little in this patient’s clinical presentation
to suggest that initial imaging should have been
recommended.
At the patient’s first follow-up visit, he reported
substantial improvement in his headaches with the
amitriptyline, and almotriptan worked well for those
that did occur. The patient’s parents, however, were
very concerned about his headaches and requested
neuroimaging. The physician ordered an MRI scan
of the head, which showed a right parietal mass.
Additional workup identified this as a low-grade
astrocytoma.
How do you reconcile this finding with the
fact that neuroimaging is not recommended
in cases of stable headache that meet
criteria for migraine?
This is certainly a startling finding. A single case
like this can have a disproportionate effect on a
57
 Chapter 4: Imaging and lumbar puncture
physician’s beliefs about diagnostic testing. Had this
finding been undetected at the initial headache eval-
uation and come to light later on, it is likely that the
family would have considered that an important diag-
nosis had been delayed or missed. Low-grade astrocy-
tomas are slow-growing glial tumors that occur most
frequently in younger people. Since they can undergo
malignant transformation, treatment of some type is
usually recommended and prolonged survival is pos-
sible. It seems likely that the fortuitous discovery of this
patient’s tumor improved his long-term outcome.
Should an event like this change your
practice? Since it is never possible to be
certain a patient doesn’t have something
seriously wrong, shouldn’t we image
everyone with headache?
There is no right or wrong answer to these ques-
tions; rather, they are something that individual doc-
tors must decide for themselves. We believe that physi-
cians should think very carefully before adopting an
indiscriminate approach to testing in order to reduce
liability risks. Medical ethics experts have pointed out
that defensive testing “essentially transfers test utility
from the patient (for care) to the physician (for self-
protection).” This is in conflict with the physician’s
professional obligation to put the patient’s interests
ahead of his or her own. Since diagnostic testing can
expose patients to harm, ordering tests that are not
indicated also is in conflict with the physician’s ethical
obligation to “first do no harm.”
Finally, it is not clear that such an approach really
does reduce the risk of a malpractice lawsuit, since
numerous studies show that the likelihood patients
will file a malpractice suit has little to do with actual
malpractice or the extent of harm suffered. Extensive
reliance on testing is probably more common among
less capable physicians. One study of test-ordering
behavior among neurologists found that older doc-
tors, those who felt more confident in their diagnoses,
and those who were board certified ordered fewer
tests.
Discussion
Physicians can be strongly influenced by unusual or
especially dramatic cases, and falsely perceive them to
58
be more common than they are. Such cases tend to
stick in the memory and are easily recalled. This is
sometimes called “availability bias” because these diag-
noses are easily “available.” It is not difficult to imag-
ine that this particular case, in which a serious prob-
lem was found in a patient who had little indication for
scanning, might reinforce a doctor’s belief that “every-
one should be scanned because otherwise you might
miss something.”
“Defensive medicine” refers to the practice of
ordering tests that are not medically indicated in order
to protect the physician from an accusation of medi-
cal malpractice if rare but serious disorders are missed;
in other words, situations such as the case described
in this vignette. It would be difficult, perhaps impos-
sible, to convince a jury that the headaches experi-
enced by a patient such as this one were really due to
migraine, especially in hindsight and with an abnor-
mal test result. Should the possibility of rare, serious
disorders lead doctors to order extensive diagnostic
testing “just in case?”
Several features of this case suggest that the
tumor was unrelated to the patient’s headache prob-
lem and represented an incidental imaging find-
ing. This patient’s history is consistent with long-
standing migraine that began at a time when he
could not have had a brain tumor. It is also unlikely
that a tumor like this would present as episodic
migraine followed by transformation to a chronic
pattern. Finally, his headaches improved with treat-
ment aimed at migraine. Taken as a whole, it seems
far more likely that the tumor, at the time it was
detected, was asymptomatic. In fact, further his-
tory in this patient is that although he had tran-
sient improvement in headaches once the tumor was
removed, headaches returned rapidly after surgery and
resumed a chronic pattern. He reestablished care in
the headache center for management of his chronic
migraine.
Thus, we do not think that this case stands as evi-
dence that all patients should be scanned in order to
avoid missing rare events. Rather, it is a reminder that
“uncommon events occur uncommonly” but can pro-
duce an outsized impact that may tend to sway us from
our principles.
Diagnosis
Chronic migraine; incidental low-grade astrocytoma.

Tip
It is not practical, possible, or desirable to image all
patients with headache. We recommend that doc-
tors stick to their principles and image only when
indicated.
Severe, sudden headache while
mowing the lawn
Case
A 44-year-old woman presented to the emergency
department one hour after the sudden onset of an
extremely severe, generalized headache. The headache
occurred while she was mowing the lawn on a warm
summer day. There was associated nausea and mild
photophobia but no phonophobia, and the pain was
so severe she didn’t want to move. She denied any
aura prior to the headache. She had a remote history
of migraine in her 20s but no significant headaches
recently. She reported that this headache was very dif-
ferent from her previous migraines.
What is the clinical term used to describe
the sudden onset of extremely severe
headache, and what is the differential
diagnosis?
The sudden onset of extremely severe headache is
referred to as “thunderclap headache.” The classic clin-
ical scenario is a headache that reaches maximal inten-
sity within seconds or minutes of onset. Thunderclap
headache is a clinical presentation rather than a diag-
nosis, and the list of entities that can cause it is exten-
sive (see Table 4.1). The experience is so dramatic that
it is often likened to being hit by lightning (perhaps a
more illustrative image than a peal of thunder!)
Both primary and secondary disorders can cause
thunderclap headache. The best known and most-
feared cause of thunderclap headache is subarachnoid
hemorrhage, and initial workup appropriately focuses
on this possibility. Other causes include intracerebral
hemorrhage, reversible cerebral vasoconstrictive syn-
drome (RCVS), arterial dissection, stroke, and cerebral
venous thrombosis. This long list of possible vascular
sources means that a good rule of thumb in formulat-
ing a differential diagnosis for thunderclap headache
Chapter 4: Imaging and lumbar puncture
Table 4.1. Selected causes of thunderclap headache
r Primary
r
Primary thunderclap headache
r
Exertional headache
r
Cough headache
r
Headache associated with sexual activity
r Secondary
r
Reversible cerebral vasoconstrictive syndrome (RCVS)
r
Subarachnoid hemorrhage
r
Intracerebral hemorrhage
r
r
Cerebral venous thrombosis
Arterial dissection
r
Stroke
r
r
Pituitary apoplexy
Colloid cyst
is to “think blood vessels.” Nonvascular causes of
thunderclap headache do exist, though. These include
large colloid cysts which can intermittently block the
third ventricle (producing transient hydrocephalus),
and pituitary apoplexy.
If secondary causes of thunderclap headache are
ruled out, several primary headache disorders that
can sometimes present in this way should be con-
sidered. These include headaches provoked by activ-
ity (such as exertional headache, cough headache, and
headache associated with sexual activity) as well as pri-
mary thunderclap headache. More controversial is so-
called “crash migraine.” This is an informal diagnos-
tic term used by some headache experts to describe
migraine attacks that build up quickly to peak inten-
sity, rather than exhibiting the more gradual increase
in pain intensity that is more common in migraine.
For the patient described in this vignette, all of
these diagnoses must be considered. In particular,
her previous history of migraine does not protect her
against the many secondary causes of thunderclap
headache. She requires urgent evaluation for danger-
ous causes of thunderclap headache, and the investiga-
tion should be as thorough as it would be in a patient
with no prior history of headaches.
What workup should she have?
All patients presenting to the emergency department
with thunderclap headache, including this patient,
should have a noncontrast-enhanced CT of the head to
evaluate for subarachnoid hemorrhage. It is well estab-
lished that CT may be negative in 5% of cases of sub-
arachnoid hemorrhage, however, so a follow-up LP in
this situation is mandatory. False-negative findings on
59
 Chapter 4: Imaging and lumbar puncture
Figure 4.1 One image from a CT angiogram showing multifocal
segmental areas of vascular narrowing that can be associated with
reversible cerebral vasoconstrictive syndrome (RCVS).
LP can occur, however, since xanthochromia may not
be seen until several hours after the initial develop-
ment of headache. This means that visual inspection
may not detect xanthochromia when LP has been per-
formed very early after onset of headache. Spectropho-
tometry is helpful in these cases.
Even when subarachnoid hemorrhage has been
ruled out by appropriate investigation, however, fur-
ther diagnostic testing should be strongly consid-
ered. Reversible cerebral vasoconstrictive syndrome is
increasingly recognized as a frequent cause of thun-
derclap headache. In RCVS there is segmental con-
striction of cerebral arteries, which produces a classic
beaded appearance of the vessels. Typically this con-
striction begins in the distal vessels and spreads proxi-
mally. RCVS (as well as arterial dissection) can be rec-
ognized with MRI and MRA. Depending on the his-
tory, a magnetic resonance venogram may also be war-
ranted. In the patient described in the vignette, the
initial CT and LP were normal but a CT angiogram
(Figure 4.1) demonstrated the characteristic beading
appearance of RCVS.
Discussion
Thunderclap headache is an important presentation
of headache in emergency settings. In our experi-
ence, most physicians are aware of the importance of
60
obtaining a head CT in this setting, and most also
would perform an LP if the CT is negative. In contrast,
fewer physicians seem to be aware of RCVS or other
potentially dangerous causes of thunderclap headache.
Nonetheless, we believe that the standard of care in
such cases is evolving rapidly and that it is prudent
to perform additional testing when the CT and LP are
normal in patients with thunderclap headache.
This level of diagnostic testing is justified because
many of the conditions which cause secondary thun-
derclap headache are life-threatening. If RCVS is
suspected it is useful to obtain a detailed history
of recent substance use. Vasoconstrictive substances,
both prescribed and illicit, are often associated with
RCVS. Patients should be carefully questioned about
the use of sympathomimetic agents such as decon-
gestants or cocaine. Selective serotonin reuptake
inhibitors and selective serotonin–norepinephrine
reuptake inhibitors, as well as marijuana, are also sus-
pected of being occasional causes of RCVS.
Treatment of thunderclap headache depends on
the underlying cause. If RCVS is found or strongly sus-
pected despite negative imaging, most clinicians would
consider the use of a calcium channel antagonist such
as verapamil or nimodipine. If secondary causes of
thunderclap headache have been convincingly ruled
out, treatment for a primary cause is usually in order.
This may include the use of calcium channel antag-
onists or such things as indomethacin if exertional
headache is suspected. Reassurance is also important;
most cases of drug-induced or primary thunderclap
headache resolve spontaneously, usually within a few
months. Avoidance of vasoconstrictive medications
during this period of time is important, however. Evi-
dence is lacking, however, about whether avoidance
of vasoconstrictive substances should be continued
beyond this period of time.
Diagnosis
Reversible vasoconstrictive syndrome (RCVS) pre-
senting as thunderclap headache.
Tip
Thunderclap headache is a clinical presentation rather
than a diagnosis. Workup of thunderclap headache in
the emergency department begins with a noncontrast
head CT and LP; if these are negative an MR or CT

angiogram should be strongly considered to assess for
RCVS.
Incidental white matter lesions in
a migraineur
Case
A 34-year-old woman reported intermittent headaches
since age 14. About three-quarters of headaches were
preceded by visual aura lasting roughly 45 min-
utes. On four occasions these visual symptoms had
lasted six to eight hours. Upon hearing this history,
the patient’s primary care physician was concerned
about the possibility of a stroke or other intracra-
nial lesion and ordered an MRI scan of the head. The
MRI report described “several small areas of abnor-
mal increased signal seen in the white matter of the
hemispheres bilaterally on the T2 and FLAIR (fluid
attenuated inversion recovery) sequences. This can
be seen in migraine but other demyelinating pro-
cess cannot be entirely excluded. Clinical correlation
is advised.” Despite an explanation that isolated T2
hyperintensities are commonly found in people with
migraine and are not worrisome, the patient did not
seem reassured. She later called to request testing
for Lyme disease and referral to a multiple sclerosis
specialist.
What is known about white matter lesions
in people with migraine?
White matter lesions on MRI brain scans are more
commonly found in migraineurs than the general pop-
ulation. A Dutch population-based study showed that
patients with migraine were more likely than controls
to have deep white matter lesions. The increased risk of
white matter lesions in migraineurs was also found in
a meta-analysis of case–control studies. A number of
studies have also suggested an increased risk of cere-
bellar infarcts in migraineurs.
In the Dutch study, the risk of white matter lesions
was greater for patients with migraine with aura (com-
pared to no aura) and in those with higher attack fre-
quency (at least 12 attacks per year). After nine years
of follow-up, the original lesions persisted but had not
increased in size. However, women with migraine had
an increased incidence of new white matter lesions, but
the overall volume of lesions remained low. There was
Chapter 4: Imaging and lumbar puncture
no evidence of such progression in men, and migraine
was not associated with progression of other brain
lesions. There also was no association between the
presence of white matter lesions and cognitive pro-
cessing or speed. This finding is consistent with evi-
dence from a French study that showed no association
between migraine and the risk of dementia or cogni-
tive impairment.
Is any further workup or treatment
required?
If the white matter lesions are small, few in number,
and the patient has no symptoms other than migraine,
as with the patient in this vignette, no further workup
is recommended. If the lesions are extensive, large,
or distributed in locations that are characteristic of
specific demyelinating disease, additional investiga-
tion may be warranted. White matter lesions seen on
MRI have a broad differential diagnosis. Etiologies to
consider include multiple sclerosis, cerebral autosomal
dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL), mitochondrial dis-
ease, vasculitis, or infectious etiologies such as Lyme
disease. Many of these disorders have characteristic
appearances on imaging. Most patients with these dis-
orders also have accompanying neurologic signs and
symptoms in addition to headache which suggest a
diagnosis other than migraine.
There is no specific treatment for white matter
lesions. Obviously, treatment of the headache disor-
der that the patient initially presented with is usually
advisable. It is unknown whether preventive treatment
of migraine might decrease the risk of developing new
white matter lesions. The use of triptans or ergots is not
contraindicated in patients with white matter lesions,
since the use of these medications has not been asso-
ciated with their development. However, some stud-
ies showed that patients with white matter lesions had
more cardiovascular risk factors than those without,
for example smoking or hypertension. It remains pos-
sible that there are subgroups of migraineurs who are
at elevated risk of not only white matter lesions but also
ischemic brain lesions. Thus, it is prudent to search for
and address modifiable cardiovascular risk factors in
patients with migraine.
There is no evidence to support the use of
antiplatelet or antithrombotic therapy such as low-
dose aspirin in migraine patients with white matter
61
 Chapter 4: Imaging and lumbar puncture
lesions. In fact, a recent analysis of data from the
Women’s Health Study showed that women who had
migraine with aura randomized to daily aspirin had an
increased risk of myocardial infarction compared with
those who did not receive aspirin. In view of this find-
ing, we do not recommend aspirin therapy in patients
with migraine who have white matter lesions and no
other indication for aspirin therapy.
Discussion
Patients with migraine who have scattered small
white matter lesions on MRI can be reassured that the
lesions do not indicate a dangerous underlying con-
dition. It can be difficult to reassure patients, however,
if this finding is unexpected, and particularly when
the radiologist’s report mentions possible diagnoses
such as multiple sclerosis. This is a situation where
discussing possible test results with patients before a
scan is ordered can help allay anxiety when results
come back. When ordering an MRI scan of the brain,
for example, we routinely tell patients that it is not
uncommon to find “white bright spots” on the MRI.
We tell them that the importance of these findings is
not known for sure, but that we do not believe they
are anything to worry about.
It is not clear why white matter lesions occur in
migraineurs. Evidence is conflicting about whether
the presence of a right-to-left cardiac shunt (such as
patent foramen ovale) is associated with a greater
burden of white matter lesions. Some theorize that
the lesions are caused by transient localized hypo-
perfusion during migraine or migraine aura, possibly
caused by oligemia of the deep penetrating vessels, or
by neuronal hyperexcitability. An alternative hypothe-
sis is that migraine and migraine aura are associated
with increased permeability of small meningeal ves-
sels, perhaps triggered by cortical spreading depres-
sion, the phenomenon generally accepted as the patho-
physiologic process underlying migraine aura. This
breakdown in the blood–brain barrier could theoret-
ically allow neurotoxic substances into the surround-
ing white matter, which might act in unknown ways to
cause white matter lesions.
Diagnosis
Migraine with aura.
62
Tip
Nonspecific white matter FLAIR hyperintensities are
often seen on MRI in patients with migraine and if the
pattern is not suggestive of another disorder, no fur-
ther workup or treatment is required. Patients should
be reassured that these lesions are common and are not
associated with any adverse outcomes.
Familial occurrence of white
matter lesions
Case
A 44-year-old woman was referred to the headache
clinic for evaluation of an abnormal MRI brain scan.
The patient reported a three-month history of near-
daily headaches in the context of substantial work and
family stress. Headaches were located behind both eyes
and were mild or moderate in intensity and described
as “squeezing, like a hat that’s too tight.” She felt cog-
nitively “fuzzy” during headaches but had no nausea,
vomiting, or sensitivity to light or sound. Headaches
responded well to ibuprofen. The headaches were get-
ting better and her preference was not to add addi-
tional treatment. She had been referred because her
primary care doctor ordered an MRI scan of the head
to assess her headaches. The scan (Figure 4.2) showed
white matter abnormalities that were felt by the radi-
ologist to be unusual for her age.
What is the differential diagnosis of this
pattern of white matter abnormalities?
The list of conditions that can produce white matter
abnormalities is very long. These lesions can be seen in
demyelinating conditions; with inflammatory or neo-
plastic processes; as a result of trauma; or in associ-
ation with congenital, metabolic, toxic, degenerative,
or vascular disorders. This patient has no hyperten-
sion, is not a smoker, and does not have diabetes. Test-
ing for Lyme disease and coagulopathies was nega-
tive. Her neurologic examination was normal with the
exception of a blunted affect and some subtle cognitive
abnormalities.
The patient reported that her 71-year-old mother
had experienced troublesome headaches for many
years, and had recently developed cognitive prob-
lems. Her mother had radiation therapy for a

Figure 4.2 An MRI showing extensive white matter lesions in a
44-year-old woman.
pituitary tumor over a decade ago. Two years ago
she had developed confusion and the family had her
evaluated for dementia. A meningioma was found
and removed, but the cognitive problems persisted.
The patient remarked that her mother “also had some
other abnormalities on her MRI scan” but could not
recall what they were.
What is the next step?
This patient’s white matter lesions are extensive for her
age. This in conjunction with her mild cognitive abnor-
malities and the report of headache and MRI abnor-
malities in her mother raise the possibility of a famil-
ial syndrome. The next step in this case was to obtain
the mother’s MRI scan for comparison. The list of
genetic disorders that manifest as white matter abnor-
malities in conjunction with headache is quite short,
and consists of mitochondrial abnormalities (such
as mitochondrial encephalomyopathy, lactic acido-
sis, and stroke-like episodes [MELAS] and myoclonic
epilepsy with ragged red fibers [MERFF]) or neuro-
cutaneous disorders such as neurofibromatosis. These
disorders can usually be easily distinguished from
Chapter 4: Imaging and lumbar puncture
Figure 4.3 The MRI scan of the patient’s mother, showing
extensive white matter lesions of a size and distribution compatible
with a diagnosis of CADASIL.
CADASIL, however, by associated physical examina-
tion findings and laboratory testing. In this case, the
mother’s scan (Figure 4.3) shows extensive white mat-
ter lesions of a size and distribution compatible with a
diagnosis of CADASIL.
Discussion
CADASIL is a genetically determined disorder caused
by a NOTCH3 mutation on chromosome 19. Ini-
tial symptoms can include migraine-like headaches
or vague psychiatric symptoms. The disorder usually
presents with brain dysfunction but it is actually a
systemic disorder, due to abnormal accumulation of
the NOTCH3 protein in vascular smooth muscle and
the brain. A single-gene, autosomal recessive form of
arteriopathy with similar clinical manifestations has
recently been discovered and termed CARASIL (cere-
bral autosomal recessive arteriopathy with subcortical
infarcts and leukoencephalopathy).
Molecular genetic testing can be done for
CADASIL to identify the NOTCH3 gene. Skin biopsy
can also be diagnostic, since NOTCH3 protein accu-
mulates at the cytoplasmic membrane of smooth
muscle in peripheral as well as cerebral blood vessels.
63
 Chapter 4: Imaging and lumbar puncture
The biopsy specimen, however, needs to be deep
enough to include material from the border zone
between the deep dermis and the upper subcutis. This
patient was offered referral for genetic counseling
and possible testing for CADASIL but declined the
referral. She preferred to adopt a “watchful waiting”
approach.
Diagnosis
Probable CADASIL.
Tip
Extensive white matter abnormalities in conjunc-
tion with a family history of headache and neuro-
logic abnormalities should prompt consideration of a
genetic syndrome.
A young man with headache following
lumbar puncture
Case
A 28-year-old man who had an LP developed a
headache within 12 hours of the procedure. It wors-
ened within a few minutes when he stood upright and
improved rapidly when he lay flat. It was associated
with nausea and photophobia. The pain was severe.
He was treated conservatively with bed rest, hydra-
tion, and caffeine for several days but the headache
did not improve. On the basis of his clinical presenta-
tion, a diagnosis of post-dural puncture headache was
made. He underwent a blood patch which provided
some relief of headache for a day, but it then returned
full force. His neurologic examination was benign. A
gadolinium-enhanced MRI of the brain showed flat-
tening of the pons and pachymeningeal enhancement.
(Similar to changes depicted in Figure 4.5, although
that is not the scan of this patient.)
Did this patient need neuroimaging or
additional testing?
This patient had postural headache that occurred
immediately following dural puncture. He had no
additional features such as fever or focal neurologic
findings that suggested an ominous cause of headache.
The most likely diagnosis was post-dural puncture
headache due to a persistent spinal fluid leak.
64
Diagnostic criteria for post-dural puncture
headache do not require confirmation of the diagnosis
with neuroimaging or other testing in the setting of
a known dural puncture that is followed within five
days by a postural headache. The criteria specify that
the headache should worsen within 15 minutes of
standing up, and improve within 15 minutes of lying
down. One of the following must also be present:
nausea, photophobia, hypacusia, tinnitus, or neck
stiffness. Finally, the headache must improve sponta-
neously within a week or within 48 hours of effective
treatment of the leak.
Thus, neuroimaging was not required to make the
diagnosis in this case. It did, however, show charac-
teristic abnormalities that supported a diagnosis of
post-dural puncture headache, in this case brain sag-
ging and diffuse pachymeningeal enhancement on an
MRI with gadolinium. Similarly, a demonstration of
low cerebrospinal fluid (CSF) pressure on LP is not
required to make a diagnosis of post-dural puncture
headache. If there is no history of a dural puncture,
however, then confirmation of a diagnosis of low CSF
pressure headache requires at least one of the following
to be demonstrated: pachymeningeal enhancement on
MRI, evidence of a CSF leak (with myelography or cis-
ternography), or a CSF opening pressure of less than
6 mm Hg in the sitting position on LP.
Since the epidural blood patch was only
temporarily successful, should this patient
be treated with an epidural saline infusion
or intravenous caffeine?
Epidural saline infusions, intravenous caffeine, and the
use of abdominal binders are all treatments that have
been reported helpful in cases of low CSF pressure
headache. Before resorting to such measures, though,
it is appropriate to repeat the epidural blood patch.
A recent Cochrane review confirmed the benefits of
epidural blood patches for treatment of post-dural
puncture headache. Epidural blood patches should be
done with at least 20 mL of autologous blood, which
is typically injected one segment below the level of the
dural puncture. The blood is thought to form a fibrin
clot over the dural tear so that healing can occur. If a
first blood patch does not succeed, a second one should
be performed, and many experts would repeat this a
third time if needed. A day or so of bed rest following

the patch is often recommended although there is no
strong evidence that this improves outcomes.
Pharmacologic therapy can be helpful when
an epidural blood patch is ineffective. A recent
Cochrane review concluded that caffeine is more
effective than placebo for treating post-dural puncture
headache. Theophylline, gabapentin, and hydrocor-
tisone decreased pain severity scores compared with
usual care or placebo. Evidence was uncertain for the
effectiveness of sumatriptan or adrenocorticotropic
hormone (ACTH). The role of intravenous fluids in
treatment of post-dural puncture headache is also
uncertain.
Discussion
The decreased volume of CSF that results from a
spinal fluid leak causes headache through traction
and tugging on pain-sensitive structures such as the
large vessels of the brain. It also results in pachy-
meningeal enhancement on MRI because of com-
pensatory engorgement of venous structures, which
expand to fill the void caused by low levels of CSF.
Almost a quarter of patients with low CSF pressure
documented on LP, however, have normal imaging
findings.
The use of smaller gauge pencil-point needles
(rather than cutting needles) when performing an LP
appears to reduce the incidence of post-dural punc-
ture headache. Routine bed rest following LP does
not appear to decrease the likelihood of post-dural
puncture headache. Although blood patches are effec-
tive for treating post-dural puncture headache once it
has occurred, evidence does not support using blood
patches prophylactically to prevent the problem.
Diagnosis
Post-dural puncture headache.
Tip
Neuroimaging is not required to make a diagnosis of
low CSF pressure headache in the setting of a known
dural puncture followed by postural headache. If a first
epidural blood patch is not successful, it should be
repeated with a larger volume of blood up to three
times.
Chapter 4: Imaging and lumbar puncture
A college student with malaise and a
change in headache pattern
Case
A young male college student and athlete with a his-
tory of episodic migraine without aura sought eval-
uation for a recent change in headache pattern. He
reported malaise and a three-day generalized, non-
descript headache of moderate severity. He contin-
ued to attend class but was not concentrating well and
was not able to exercise because it made his headache
worse. On examination, he was afebrile but his neck
was slightly stiff. Because he was very muscular, the
physician thought this might be due to an inability to
relax his neck muscles during the examination, which
was otherwise normal. The physician considered per-
forming an LP but recalled the patient he had seen ear-
lier in the day who developed a post-dural puncture
headache. She had been angry and reported that none
of her prior headaches had been as bad as “the one you
gave me.” The physician advised the college student
that his symptoms were likely to be from viral menin-
gitis, were probably benign, and should respond to rest
and analgesic medication.
When should a lumbar puncture be
performed for the evaluation of headache?
The broad answer is that LP should be considered
in the evaluation of any patient where the physician
suspects a possible hemorrhage, infection, malig-
nancy, or alteration in spinal fluid pressure as a pos-
sible cause of headache. When an LP is performed,
it is routine to order laboratory testing of the fluid
that includes a cell count on the first and last (usu-
ally the fourth) tubes of spinal fluid obtained, a spinal
fluid protein level, and glucose determinations as well
as infection-related testing. Additionally, the physician
may order other special studies depending on the indi-
vidual patient’s situation. In our view, an opening pres-
sure should be obtained routinely in all patients under-
going LP for the evaluation of headache, and the result
should be recorded in the chart; a closing pressure can
be obtained as well if warranted, which is usually in the
setting of elevated intracranial pressure.
It can be challenging to decide when there is suf-
ficient suspicion of one of these secondary headaches
to warrant performing an LP. The possibilities of
adverse effects of the LP, particularly post-dural
65
 Chapter 4: Imaging and lumbar puncture
puncture headaches, weigh heavily in this decision.
The overall severity of the clinical situation and an
assessment of how sick a patient is are both commonly
taken into account. When the physician is still unde-
cided, a clinical pearl that has been passed on from
senior to younger physicians is that “the indication for
an LP is whenever you think of it.” In other words,
experienced physicians have learned that it is impor-
tant to maintain a high index of suspicion for danger-
ous illnesses that can only be diagnosed by LP.
The patient described in this vignette had a wit-
nessed seizure at home later that night. He was taken
to the emergency department where a CT of the head
was negative but an MRI of the brain showed subtle
bitemporal enhancement. His spinal fluid test results
were consistent with a viral process. Antiviral therapy
was started. Polymerase chain reaction (PCR) testing
for herpes simplex virus (HSV) was later reported as
positive. The patient was diagnosed with herpes sim-
plex encephalitis and eventually recovered.
Was the hesitance to perform a lumbar
puncture in this patient warranted?
Post-dural puncture headache is a complication of LP
that occurs in up to 30% of procedures. The likelihood
of this problem, and physician memories of unhappy
patients who have experienced this complication, may
make some physicians reluctant to perform the pro-
cedure, especially when secondary pathology is not
highly suspected and the study is being considered
simply to “rule out” other more serious conditions. On
the other hand, in this particular case, the physician
involved probably weighed the risk of post-dural punc-
ture headache too highly based on his recent and eas-
ily recalled adverse experience with another patient.
This is another example of availability bias, in which
memorable events are easily recalled and erroneously
thought to be more likely or common than is the case.
Discussion
Risk factors for the development of post-dural punc-
ture are listed in Table 4.2. Some, such as the choice
of needle used in the procedure, are modifiable, but
others, such as patient sex, are not. Migraineurs may
be at increased risk for post-dural puncture headache,
so it is especially important that the pre-procedure
informed consent discussion includes a review of post-
dural puncture headache.
66
Table 4.2. Selected risk factors for headache following
dural puncture
r Female sex
r Age between 31 and 50 years
r Prior history of post-dural puncture headache
r Use of a cutting needle (e.g. Quinke)
r Needle size
r Cutting needle bevel orientation perpendicular to the
long axis of the spinal column during the procedure
It is unknown whether post-dural puncture
headaches in migraineurs last longer or are more
difficult to treat than in non-migraineurs, but our
clinical experience suggests this might be the case.
Fortunately, there is no evidence to suggest that
the development of post-dural puncture headache
will have a lasting negative effect on the patient’s
headache pattern. Thus, the decision to perform an
LP in situations that warrant it should not depend
on whether the patient has a history of migraine.
The physician in this vignette was clearly hoping
to avoid adding to this patient’s existing burden of
headache by avoiding a post-dural puncture headache.
Unfortunately, his reluctance to perform an indicated
diagnostic procedure led to a delay in diagnosis of a
serious condition.
It is our impression that, for a variety of reasons,
LP is an underused diagnostic procedure in a refer-
ral headache clinic and even emergency department
settings. Careful attention to optimal procedural tech-
nique, as described in the next vignette, could improve
both the clinician’s and patient’s experience with LP
and decrease reluctance to perform it when indicated.
Diagnosis
Herpes simplex encephalitis.
Tip
Indicated diagnostic procedures such as LP should
not be avoided in migraineurs because of a fear of
complications.
Optimizing the performance of
lumbar puncture
Case
A physician was covering the neurology consulta-
tion service of his local hospital one weekend. A

spinal cord
epidural space
L3
L4
subarachnoid
space
Figure 4.4 Anatomy of a lumbar puncture.
first-year resident approached him and explained that
she needed to perform an LP on a patient she had just
admitted. She was not confident of her ability to do the
procedure and asked if the physician could “walk her
through” the technique.
How do you advise the resident?
LP is considered a routine medical procedure and most
physicians gain experience performing LPs in their
first post-graduate year. As with the resident in the
vignette, though, most residents rely on advice and
guidance from senior physicians to learn how to per-
form the procedure, which they then perfect through
trial and error. The use of simulation-based training
techniques has been shown to improve the perfor-
mance of LP in clinical settings, but not all training
programs provide simulator training. Figure 4.4 illus-
trates the anatomic structures and approach to doing
an LP. There are many descriptions in the medical lit-
erature of the techniques for performing LPs. The fol-
lowing is a description of our preferred approach.
Procedure
1. Obtain informed consent; discuss with the patient
the possibility of complications, including
post-dural puncture headache, bleeding, or
infection, and how those complications would be
handled.
Chapter 4: Imaging and lumbar puncture
2. Explain the major steps of the procedure, how the
patient will be positioned, and review aftercare
recommendations.
3. Have the patient lie on an examining table or bed
in the lateral decubitus position with knees curled
up to the chin, or if seated ask them to lean over a
solid surface on which they rest their elbows,
since these positions spread the vertebrae and
create maximum space between the interspinous
processes.
4. Palpate for landmarks over the spinous processes
at L4–5, L3–4, or L2–3 levels. If these cannot be
palpated, locate the sacral promontory, which
marks the interspace of L5–S1. Use this
reference to locate L4–5 for the entry
point.
5. Sterilize and drape the area after identifying
landmarks. Use lidocaine 1% with or without
epinephrine to anesthetize the skin and the
deeper tissues under the insertion site.
6. Assemble needle and manometer. Attach the
3-way stopcock to manometer.
7. Insert LP needle through the skin and advance
through the deeper tissues. A slight pop or give is
felt when the dura is punctured. The angle of
insertion should be slightly towards the navel,
between the vertebrae. If you hit bone, partially
withdraw the needle, reposition, and
re-advance.
8. When CSF flows, attach the 3-way stopcock and
manometer. Measure intracranial pressure, which
should be 20 mm H2 O or less. Remember that
any pressure reading performed when the patient
is sitting will be unreliable.
9. If CSF does not flow, or you hit bone, withdraw
needle partially, recheck landmarks, and
re-advance.
10. Once the pressure has been recorded, remove the
3-way stopcock, and begin filling collection tubes
1–4 with 1–2 mL of CSF each:
a. Tube 1: glucose, protein, protein
electrophoresis, cell count
b. Tube 2: Gram’s stain, bacterial and viral
cultures
c. Tube 3: cell count and differential
d. Tube 4: reserve tube for any special tests.
11. After tap, remove needle, and place a bandage
over the puncture site.
67
 Chapter 4: Imaging and lumbar puncture
a. Document the procedure in the patient’s
medical record.
b. Include in your note a brief history and
physical examination of the patient, the
reasons for performing the LP, and consent.
Note in particular a brief examination of the
cranial nerves, presence or absence of
papilledema, or any other lateralizing
neurologic finding. Also include a brief note
of examination of the patient’s spine with
attention to any obvious spinal deformity.
c. Document position of patient during the
procedure, opening pressure, and clarity/color
of the CSF. Once results of the CSF analysis
are available, they can be appended to your
note.
Are there guidelines for the performance of
lumbar puncture?
The American Academy of Neurology has published
recommendations for the performance of LP. These
suggest: (1) using the smallest needle size possible; (2)
using noncutting atraumatic 22 gauge Sprotte spinal
needles to reduce the frequency of post-dural puncture
headache. If noncutting needles are used, the stylet
should be replaced before the needle is withdrawn
from the intradural space. (3) Keeping bevel orienta-
tion parallel to the long axis of the spinal canal if cut-
ting needles are used. (4) Bed rest or fluid loading have
not been shown to reduce the risk of post-dural punc-
ture headache, so it is not necessary to limit activity
after the procedure.
Misinterpreting the workup in low CSF
pressure headache
Case
A 68-year-old male presented with a persistent
headache of six months’ duration. There was no past
personal or family history of migraine. There was
no history of trauma or instrumentation. Initially he
had noticed a brief intermittent global headache trig-
gered by coughing and at times associated with neck
pain and tinnitus. The headache progressed to become
daily with or without trigger but had cleared com-
pletely within five minutes when the patient lay down.
68
The headache was absent when he awakened in the
morning but would recur within ten minutes after the
patient got out of bed. A noncontrast head CT scan
was normal. Low CSF pressure headache was consid-
ered as a diagnosis but excluded when a normal CSF
opening pressure was found on LP and a normal CSF
tracer study showed no apparent leak. The patient was
diagnosed with cervical degenerative disease and cer-
vicogenic headache. He unsuccessfully tried a vari-
ety of treatments, including nerve blocks and facet
joint injections, and when seen in follow-up was no
better.
Is cervicogenic headache the best diagnosis
in this patient?
Certainly this story is more suggestive of a secondary
headache than of migraine, and given the patient’s
age it was almost a certainty that testing would show
some osteoarthritis of the neck. There is, however,
very little specific history or diagnostic information
in his case to suggest cervicogenic headache as a
likely diagnosis. The term cervicogenic headache is
used to describe a disorder of the cervical spine or
adjacent structures that produces pain referred to the
head or face. Apart from the finding of degenerative
changes consistent with cervical spondylosis, there is
little here to suggest cervical pathology as the cause of
the patient’s headache. Furthermore, cervical spondy-
losis and osteochondritis, since they are so commonly
present asymptomatically, are explicitly mentioned
in International Classification of Headache Disorders
(ICHD)-3 beta as conditions that “may or may not be
a cause of cervicogenic headache.” In this patient, who
has no physical findings of decreased cervical range
of motion or worsening of headache with provoca-
tive neck maneuvers, cervicogenic headache does not
seem a likely diagnosis. In addition, the patient did
not improve with blockade of nerves supplying cer-
vical structures, which makes the diagnosis even less
likely.
What features of the history are of most
value in establishing the correct diagnosis in
this case?
Historical features of note in this case included the
positional nature of the headaches, which began
 Chapter 4: Imaging and lumbar puncture

Table 4.3. Conditions that can be missed on CT Table 4.4. Headache attributed to spontaneous intracranial
hypotension: clinical and diagnostic characteristics
r Vascular diseases including:
r
Aneurysms A headache, often but not always positional in nature and
r
Arteriovenous malformations (especially posterior fossa) usually accompanied by stiffness of the neck or hearing
r
Subarachnoid hemorrhage abnormalities
r
Arterial dissections
r CSF pressure of less than 60 mm H2 O (in the sitting position) or
Acute infarcts
r radiologic evidence of a CSF leak
Venous thrombosis
r
Vasculitis
r
Subdural and epidural hematomas
r Neoplastic diseases including:
r

r
Posterior fossa neoplasms
Meningeal carcinomatosis
r
Small pituitary tumors
r Infections:
r
Paranasal sinusitis
r
Meningoencephalitis
r
Brain abscess
r Other:
r
Low CSF pressure
shortly after rising each day, and their rapid disappear-
ance when the patient lay flat. This pattern is most
consistent with a diagnosis of headache attributed
to low CSF pressure. Practitioners often assume that
there must be a history of a prior LP or other instru-
mentation in order to consider such a diagnosis, but
there is ample evidence that spontaneous CSF leaks
can develop and lead to low pressure or volume
headache.
Although this diagnosis was considered, it was
apparently discarded based on the normal CT report,
the normal CSF opening pressure, and the normal
tracer study. However, the clinical presentation is so
characteristic of low CSF pressure headache that it is
important to consider the possibility of false-negative
or inaccurately interpreted test results. The CSF open-
ing pressure may be normal in low CSF pressure
headache when it is measured with the patient recum-
bent; taking a pressure reading with the patient in a
sitting position will often show the pressure to be low.
Tracer studies are notoriously likely to be negative in
patients who have a slow leak. And finally, CT scan-
ning is known to be inferior to MRI for demonstrating
the pachymeningeal enhancement that is seen in many
(but not all) patients with low CSF pressure headaches
(Table 4.3). Taken as a whole, the best explanation of
this patient’s headache presentation remains headache
due to low CSF pressure – despite his apparently nor-
mal test results.
Discussion
The clinical characteristics of headache due to sponta-
neous intracranial hypotension are listed in Table 4.4.
The headache is usually diffuse or dull and often wors-
ens within 15 minutes after standing. It commonly
remits, sometimes slowly, after the patient lies flat for
some time. Neck stiffness, tinnitus, diminished hear-
ing acuity, photophobia or nausea may be reported.
Diagnostically, we like to see that one or more of the
following are present: MRI evidence of low pressure,
radiographic evidence of a CSF leak, OR a CSF open-
ing pressure of less than 60 mm H2 O in the sitting posi-
tion. Although this is not the typical position for mea-
surement of CSF pressure we find that a measurement
obtained in the recumbent position may be normal in a
low CSF pressure headache. In patients who are known
to have had a procedure that might have punctured the
dura or who have MRI evidence of a low CSF pres-
sure headache, an LP to establish a low pressure is not
needed prior to treatment.
Even when the history strongly implicates a low
CSF pressure headache, it can be difficult or impos-
sible to actually detect the leak. In fact some patients
may not have an actual leak at all: patients who
have multiple dural diverticulae in the lumbar region
may sequester CSF in the diverticulae when they
are upright, leading to low CSF pressure without an
actual leak. This is sometimes termed a “compliance”
headache.
Table 4.3 lists conditions in addition to low CSF
pressure headaches that may be missed by CT but
which are usually detected by MRI. CT may be
suboptimal compared to MRI in the evaluation of a
number of central nervous system conditions; a report
of a normal head CT scan may be reassuring by indi-
cating the absence of a large mass or bleed but does
little to clarify some of the other conditions listed,
including low CSF pressure headache, and should not
be relied upon to confirm the diagnosis. In many
neurologic conditions, including suspected low CSF

69
 Chapter 4: Imaging and lumbar puncture
Figure 4.5 Gadolinium enhanced T1-weighted axial MRI showing
pachymeningeal enhancement.
pressure headache, the evaluation may be considered
incomplete in the absence of MRI scanning, although
even MRI can produce false negatives. In one study, the
sensitivity of MRI with and without gadolinium was
83%. Thus, about a fifth of patients with low CSF pres-
sure headaches will have normal MRI scans.
In this patient, an MRI scan was ordered
(Figure 4.5) and showed clear evidence of pachy-
meningeal enhancement consistent with a low CSF
pressure headache. He was treated with a 20 mL autol-
ogous epidural blood patch and experienced complete
resolution of his headaches almost immediately after
the procedure.
The characteristic MRI features of low CSF pres-
sure headache (Table 4.5) are likely to be related to the
suspected pathophysiology of the condition; in the set-
ting of reduced CSF volume and support in an upright
patient, contents of the skull may respond to gravi-
tational force producing the sagging appearance with
crowding of the posterior fossa and reduced size of
the cisterns. Downward traction on meningeal struc-
tures has been associated with increased volume of
the epidural space, leading to increased venous vol-
ume, producing the appearance of pachymeningeal
enhancement, and to increased epidural fluid, lead-
ing to hygroma formation. Diagnostic changes likely
related to pressure changes may also be apparent on
70
Table 4.5. MRI features of low pressure headache
r Diffuse pachymeningeal enhancement after gadolinium
r Cerebellar tonsillar descent
r Downward descent (sagging) of the brain/brainstem
r Crowding of the posterior fossa
r Pituitary enlargement
r Bilateral convexity subdural hygroma
r Paraspinal extra-arachnoid CSF collection
spinal MRI. Changes are enhanced with the use of
gadolinium.
Diagnosis
Headache attributed to spontaneous intracranial
hypotension.
Tip
Overreliance on the results of the wrong diagnostic
study can obscure the clinical picture and lead to pre-
mature, and unwarranted, diagnostic conclusions and
unsuccessful management. Selecting the correct study
for the suspected condition is essential.
Further reading
Radiation risks from scanning
Brenner DJ, Hall EJ. Computed tomography – an increasing
source of radiation exposure. N Engl J Med. 2007;357:
2277–84.
Mettler FA Jr., Huda W, Yoshizumi TT, Mahesh M.
Effective doses in radiology and diagnostic nuclear
medicine: a catalog. Radiology. 2008;248:254–63.
Does testing relieve anxiety?
Fitzpatrick R. Telling patients there is nothing wrong. BMJ.
1996;313:311–12.
Frishberg, BM. The utility of neuroimaging in the
evaluation of headache patients with normal neurologic
examinations. Neurology. 1994;44:1191–7.
Howard L, Wessely S, Leese M, et al. Are investigations
anxiolytic or anxiogenic? A randomised controlled trial
of neuroimaging to provide reassurance in chronic daily
headache. Neurol Neurosurg Psychiatry. 2005;76:1558–
64.
McDonald IG, Daly J, Jelinek VM, Panetta F, Gutman JM.
Opening Pandora’s box: the unpredictability of
reassurance by a normal test result. BMJ. 1996;313:
329–32.
Petrie KJ, Muller JT, Schirmbeck F, et al. Effect of providing
information about normal test results on patients’

reassurance: randomized controlled trial. BMJ. 2007;334:
352–4.
van Ravesteijn H, van Dijk I, Darmon D, et al. The
reassuring value of diagnostic tests: a systematic review.
Patient Educ Couns. 2012;86:3–8.
Defensive medicine
Birbeck GL, Gifford DR, Song J, et al. Do malpractice
concerns, payment mechanisms, and attitudes influence
test-ordering decisions? Neurology. 2004;62(1):
119–21.
DeKay ML, Asch DA. Is the defensive use of diagnostic tests
good for patients, or bad? Med Decis Making. 1998;18(1):
19–28.
Thunderclap headache
Ducros A, Bousser M-G. Thunderclap headache. BMJ.
2013;346:e8557.
Schwedt, TJ. Thunderclap headaches: a focus on etiology
and diagnostic evaluation. Headache. 2013;53(3):563–
9.
White matter lesions in migraine
Agostoni E, Rigamonti A. Migraine and small vessel
diseases. Neurol Sci. 2012;33(Suppl 1):S51–4.
Debette S, Markus HS. The clinical importance of white
matter hyperintensities on brain magnetic resonance
imaging: systematic review and meta-analysis. BMJ.
2010;341:c3666.
Kruit MC, van Buchem MA, Hofman PA, et al. Migraine as
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 Chapter
Pitfalls in diagnostic testing: blood, urine,
5 and other tests
In addition to imaging studies and lumbar puncture,
a variety of other tests can be useful in the evalua-
tion or treatment of patients with headache disorders.
Blood and urine tests are the most commonly ordered
additional tests in the headache clinic, but electrocar-
diograms, electroencephalograms, and other tests may
also be used. Such tests are most helpful in assessing
the possibility of secondary causes of headache but are
only rarely required for such a diagnosis.
Of the hundreds of headache types described in
the International Classification of Headache Disor-
ders (ICHD), only four secondary forms of headache
require blood or urine tests for a definitive diagno-
sis: urine testing is necessary to make a diagnosis
of headache due to preeclampsia or eclampsia, while
blood tests are required to make a definitive diagno-
sis of headache due to human immunodeficiency virus
(HIV) infection or hypothyroidism. For a large num-
ber of other disorders, blood or urine testing is help-
ful in making a diagnosis but not absolutely required.
A diagnosis of giant cell arteritis, for example, can be
based solely on suggestive symptoms in conjunction
with a positive temporal artery biopsy.
Laboratory testing is frequently needed to monitor
headache treatment. Lithium and verapamil, the two
most commonly used preventive treatments for clus-
ter headache, require careful monitoring to minimize
the chance of adverse events from treatment. Patients
on chronic opioid therapy also require regular moni-
toring with blood or urine tests to ensure adherence
to recommended treatment and minimize the likeli-
hood of drug diversion or other aberrant drug-related
behavior. For some drugs, monitoring of renal or liver
function tests may be advisable.
The judicious use of laboratory and other forms of
testing is an important part of the practice of headache
medicine. Because abnormal results on testing can cre-
ate anxiety and lead to further, potentially harmful,
interventions, careful consideration should be given to
the need for every test. Testing should be ordered after
consideration of the patient’s individual clinical situa-
tion, rather than ordered as part of a routine workup.
Hormone testing in women with
menstrual headaches
Case
A 36-year-old woman sought treatment because of
severe headaches associated with her menstrual cycle.
Her description of headaches was consistent with a
diagnosis of migraine and her neurologic examina-
tion was normal. The patient reported that although
she had headaches at other times of the month, they
were more likely to occur just before the onset of men-
strual bleeding. She was treating headaches with over-
the-counter ibuprofen with little success. A friend had
suggested that her problems might be due to hor-
monal abnormalities. The patient had her estrogen lev-
els checked by a naturopathic physician who told her
they were “completely off” and recommended treat-
ment with add-back bio-identical estrogen during the
perimenstrual period. The patient had tried this for
several months, but treatment was expensive and while
she thought perhaps it had been helpful for her period-
associated headaches, she still had an average of five or
six other migraines a month.
What is the patient describing and how can
that diagnosis be confirmed?
Migraine headaches that occur in predictable rela-
tion to the menstrual cycle are commonly referred
to as “menstrual migraines.” According to diagnostic
criteria in the appendix of ICHD-3 beta, menstrual
migraine attacks must occur during a five-day win-
dow of time beginning two days before and extend-
ing to three days after the onset of vaginal bleeding.
73
 Chapter 5: Blood, urine, and other tests
Furthermore, this must occur on average in two of
every three cycles. The diagnostic criteria suggest that
these attacks are without aura, and say that headaches
occurring with aura are unlikely to be associated with
menstruation.
The diagnostic criteria define “pure menstrual
migraine” as a situation in which migraine attacks
occur only during this five-day menstrual window and
at no other time of the month. In contrast, “menstru-
ally related migraine” is diagnosed when headaches
occur predictably during this five-day window but also
at other times of the month.
Confirmation of a diagnosis of menstrual migraine
requires objective evidence of the timing of headaches
in relation to the patient’s menstrual cycle. In general,
we recommend basing the diagnosis on at least three
months of headache diary records. In our clinical expe-
rience, it is very important to take the time to do this,
to identify correctly a menstrual trigger for headaches.
Patient self-report of menstrual migraine is not reli-
able. One study showed that roughly 20% of women
who self-reported a diagnosis of menstrual migraine
did not actually meet criteria for a diagnosis of men-
strual migraine when headache diaries were kept.
In this case, the patient’s headache diary showed
migraine attacks during the five-day menstrual win-
dow during all three months of recording. The patient
also had attacks at other times of the month, so she met
criteria for a diagnosis of menstrually related migraine.
Is it useful to check hormone levels in
women who have menstrual migraine?
Good evidence suggests that estrogen withdrawal is
the likely cause of menstrual attacks of migraine,
although other hormonal changes at this time of the
menstrual cycle may contribute to migraine suscep-
tibility. Estradiol levels are high following ovulation.
These high levels are sustained until the late luteal
phase of the cycle, when they fall quickly. A simi-
lar fall in estrogen levels also occurs and can provoke
headache in susceptible women during the placebo pill
week of some oral contraceptive regimens, following
childbirth, and with certain types of noncontinuous
hormone replacement regimens.
Many patients with menstrually triggered migraine
attacks wonder whether there is “something wrong”
with their hormone levels. There is no evidence, how-
ever, that treatable hormonal abnormalities are the
cause of menstrual migraine. Rather, women who have
74
inherited a migraine-prone nervous system are unusu-
ally sensitive to normal fluctuations in steroid hor-
mone levels. There is no clinical reason to check serum
levels of estrogen in women with menstrual migraine.
In this case, an emphasis on menstrual-associated
headaches meant that the patient’s many non-
menstrual headaches were ignored. The patient was
begun on 10 mg of amitriptyline daily and asked to
use eletriptan 40 mg for up to two headaches a week.
At a follow-up visit she reported that her headache
frequency was down to two headaches a month
and that those headaches were effectively treated by
eletriptan.
Discussion
Menstruation is a highly noticeable, culturally signifi-
cant recurrent event. For these reasons it is what soci-
ologists sometimes refer to as a “magnet explanation.”
In other words, events that occur in association with
menstruation are highly likely to be attributed to it,
sometimes mistakenly. This is an example of the cog-
nitive error or bias known as “illusory correlation,” in
which coincidental events are falsely assumed to be
causally related, often as a result of strongly held prior
beliefs.
In women with frequent migraine attacks,
headaches may occur in conjunction with menstru-
ation simply by chance. It is important to verify
even strongly held assumptions about the connection
between headaches and hormonal events, ideally using
a headache diary. Exclusive emphasis on hormonal
causes of headaches may limit attention to other
explanations for headache or may lead to misguided
attempts at treatment. In the case described in the
vignette, treatment aimed solely at hormonal causes
of headache did nothing to help the patient with
her many nonhormonal headaches. In contrast, all
of her headaches were successfully managed using
traditional nonhormonal migraine therapies.
Diagnosis
Menstrually related migraine.
Tip
Headache diaries, not blood or urine hormone levels,
are most helpful in making a diagnosis of menstrually
related migraine attacks, and are necessary to avoid
falsely attributing headaches to a hormonal cause. A

hormonal trigger for headaches does not mean that
treatment must also be hormonal.
Monitoring verapamil treatment in
cluster headache
Case
A 40-year-old man presented to the headache clinic for
follow-up care. He reported daily 90-minute episodes
of 10/10 right-sided retro-orbital pain with right-sided
nasal congestion and ptosis. He had been seen in the
clinic ten years earlier and diagnosed with episodic
cluster headache. Treatment with verapamil was effec-
tive and he returned to the care of his personal physi-
cian who continued to prescribe verapamil.
The patient’s cluster headache bouts typically
occurred for just three months every year but he accu-
mulated a stockpile of verapamil by filling prescrip-
tions year-round. When his personal physician retired
he used medication from this stockpile to manage
his annual bout of cluster headaches. Through trial
and error he found that a dose of 720 mg daily was
more effective than the lower doses of medication rec-
ommended by the headache clinic and his personal
physician.
At this appointment the patient said that his annual
bout of cluster headaches had begun. His neurologic
examination was normal, but on review of systems he
complained of fatigue, constipation, and shortness of
breath, noting that recently he had barely been able
to get through his workday. He attributed these symp-
toms to cigarette smoking and planned to discuss them
when he obtained an appointment with a new primary
care physician. He was about to run out of verapamil
and requested a refill.
Should this patient’s verapamil prescription
be refilled?
Verapamil is the drug of choice for prevention of
cluster headaches, although the US Food and Drug
Administration (FDA) has not approved it for that pur-
pose. In our experience, the dose of verapamil required
to suppress cluster headaches successfully is higher
than the doses that are typically used to treat other
conditions such as hypertension. Most experts begin
with a dose of 240 mg a day, either given as a once-
daily, sustained release preparation or as 80 mg three
times daily. Many patients require an even higher dose
Chapter 5: Blood, urine, and other tests
for control of headaches. One recommended titration
strategy is to increase the drug by 80 mg a day every
two weeks until headache control is gained or intoler-
able side effects occur.
These high doses increase the likelihood and
severity of side effects, which can include constipa-
tion, peripheral edema, fatigue, and heart block. The
patient in the vignette has achieved excellent con-
trol of his cluster headaches with verapamil. Although
this patient could be experiencing an unrelated or
smoking-related respiratory condition, the best option
in this case before continuing verapamil would be to
assess the patient for verapamil-related cardiac con-
duction delay, which may appear even after long peri-
ods of uneventful use.
How common are electrocardiographic
abnormalities with verapamil treatment for
cluster headache?
In one study, electrocardiographic abnormalities were
detected in about a third of patients treated for cluster
headaches with high doses of verapamil. Bradycardia
(a heart rate of ⬍ 60 beats per minute) was the most
common abnormality, followed by first-degree heart
block (PR interval ⬎ 0.2 seconds). More severe degrees
of heart block were rare. In this study, electrocardio-
graphic changes were seen with mean verapamil doses
of around 1000 mg daily and did not occur with doses
lower than 800 mg a day. Although these abnormalities
sometimes required cessation of verapamil, in many
other cases they resolved with a decrease in dose. A
reasonable monitoring strategy is to obtain an electro-
cardiogram before verapamil treatment is started, and
after each dosage increase or with the appearance of
symptoms that could have a cardiac cause.
The patient in the vignette had no history of heart
disease and an electrocardiogram done two years ago
had been normal. However, on examination at this
visit his resting heart rate was 48 beats per minute.
An electrocardiogram showed first-degree heart block
with a PR interval ⬎0.2 seconds. The dose of verapamil
was reduced to 80 mg three times daily. The patient’s
headaches did not recur and his symptoms of fatigue
and shortness of breath resolved.
Discussion
Cluster headache is characterized by attacks of severe
or very severe, strictly unilateral orbital, peri-orbital,
75
 Chapter 5: Blood, urine, and other tests
or temporal pain that last from 15 minutes to 3 hours.
During cluster periods or bouts, headaches may occur
every other day up to several times a day. Attacks
are associated with ipsilateral cranial autonomic fea-
tures such as tearing, ptosis, miosis, or rhinorrhea. In
episodic cluster headache, cluster bouts can last for
weeks or months and often recur yearly at roughly the
same time. Many patients have long periods of remis-
sion during which they are entirely free of headaches.
In contrast, patients with chronic cluster headache do
not experience remissions, or have remissions that are
very short.
Injectable sumatriptan or inhalation of 100% oxy-
gen are effective treatment for individual attacks of
cluster headache, but their use on a daily or near-
daily basis is impractical. Additionally, while wait-
ing for them to take effect patients will experi-
ence a short period of incapacitating pain, which
can severely disrupt daily life activities. Thus, essen-
tially all patients with cluster headache should also
receive preventive treatment, which is given daily dur-
ing a cluster bout to decrease or eliminate cluster
attacks.
Although verapamil is the first-line preventive
treatment for cluster headache, other preventive treat-
ments including lithium, melatonin, or the use of
occipital nerve blocks can be tried. Successful use of
verapamil may require titration to fairly high doses; a
common reason for apparent failure of this treatment
is the use of inadequate doses. In many instances doses
over 360 mg daily are required up to and including the
recommended maximum daily dose of 960 mg, doses
that are far higher than those used in the management
of cardiac conditions.
Once successful control of cluster headaches is
achieved, many patients are reluctant to discontinue
preventive treatment. Some patients with episodic
cluster headache prefer to stay on preventive treat-
ment such as verapamil year-round even if they have
attacks for only three or four months a year. While this
preference is understandable in view of the severity
of cluster headache pain, we discourage this practice.
Instead, we recommend that patients gradually lower
the dose of preventive medication as they approach the
expected time when their cluster bout should be end-
ing. If headaches recur when the dose is lowered, a
higher dose can be resumed for several more weeks,
when another attempt should be made to taper the
drug. In our experience, this is an often-overlooked
aspect of managing cluster headaches.
76
Diagnosis
Episodic cluster headache and verapamil-induced car-
diac conduction delay.
Tip
High doses of verapamil may be required for success-
ful prevention of cluster headache. Regular electrocar-
diographic monitoring is needed to avoid the adverse
effects of cardiac conduction delay.
Urine drug testing in patients
taking opioids
Case
A 37-year-old woman returned to the headache clinic
for a follow-up visit. The patient had severe post-
traumatic head and face pain following a gunshot
wound. The pain had not responded to treatment with
gabapentin, amitriptyline, or numerous other medica-
tions for neuropathic pain. Because it was relieved by
opioid medications, the patient had been started on
sustained release morphine. Unfortunately, intermit-
tent bouts of vomiting from pancreatitis made it dif-
ficult to use oral medications. At her last visit the oral
morphine was discontinued and she was started on a
fentanyl patch. The patient reported that her pain was
well controlled on the fentanyl. Along with pancre-
atic enzymes and a multivitamin she was using cariso-
prodol intermittently for episodes of muscle spasm.
Because her usual physician was on maternity
leave, the patient was seen by a resident who was rotat-
ing in the clinic. After consultation with a supervis-
ing physician, the resident refilled the patient’s fen-
tanyl prescription. He noticed that at her last visit a
pain treatment urine drug screen had been obtained,
so before the patient left he repeated this test. Later that
day the resident reviewed the test results. He was star-
tled to see that the urine drug test results did not men-
tion the presence of fentanyl but instead reported that
meprobamate, a tranquilizer, had been detected.
What are the possible explanations for these
urine findings?
Fentanyl is not reliably detected by urine or blood drug
testing, making it challenging to monitor the long-
term use of this drug. Urine drug testing is still use-
ful, though, in order to monitor the patient’s possible

use of other nonprescribed substances. In this case,
the finding of meprobamate in the urine might be
misinterpreted as a sign that the patient is taking a
nonprescribed, possibily illicitly obtained, substance.
However, carisoprodol is metabolized to meprobamate
and thus the presence of meprobamate in this patient’s
urine sample is not unexpected. It is important to be
aware of substances that can produce a false-positive
urine drug test result. It is advisable to consult with
the laboratory that you use to process the samples, to
learn what tests they use, the limits of detection, and
any other unique characteristics of the laboratory.
If this patient’s urine sample had contained evi-
dence of tetrahydrocannabinol (THC), an indication
of marijuana use, the physician would have had more
reason to be concerned. THC use is correlated with the
use of other illicit substances and some studies sug-
gest it is an indicator of high risk for abuse of opi-
oids. An exception to this would be a patient who
lives in a state where the use of “medical marijuana” is
allowed. Such patients should have received the drug
through approved channels, however, and should have
informed the physician about its use prior to drug
testing.
How else might this patient’s use of fentanyl
be monitored?
The purposes of monitoring in patients on chronic opi-
oid therapy are two-fold: (1) to ensure the patient is
benefitting from treatment; and (2) to detect prob-
lems with drug diversion or misuse. The benefits of
treatment can be established through pain ratings that
show meaningful reductions in pain intensity related
to opioid treatment. Functional improvement is also
important. Many physicians find it useful to mon-
itor such things as return to work, reduced use of
breakthrough pain medications, and fewer emergency
department visits for poorly controlled pain. When
urine or blood tests cannot reliably detect an opioid,
as is the case in this vignette, other ways of monitor-
ing compliance with long-term opioid therapy can be
used. For example, the patient’s skin can be inspected
at each visit to ascertain that the expected patches
are in place. Patients can also be asked to bring their
unused patches along to appointments to show that
these are in their possession and to ensure that the
proper number of patches remains.
Patients may perceive these forms of monitoring as
burdensome or intrusive. Before starting chronic opi-
Chapter 5: Blood, urine, and other tests
oid therapy it is important to obtain informed con-
sent from the patient for treatment and to outline in
detail the rules of your practice about opioid treat-
ment and monitoring. Most experts recommend the
use of “treatment contracts” that outline the conditions
under which the medication will be prescribed, the
methods that will be used to monitor the treatment,
and the circumstances under which lost prescriptions
will be replaced or therapy discontinued. Sample treat-
ment contracts can easily be located online. These
treatment contracts do not have legal force but do
stand as a clear record of the understanding you had
with the patient about treatment. They are valuable
if questions or disputes later arise about the patient’s
treatment.
Appropriate selection of patients for chronic opioid
therapy may help reduce the risks of diversion or mis-
use, although there is no strong evidence about this. A
number of tools can be used to identify patients who
are at high risk of aberrant drug use, including the opi-
oid risk tool, the Pain Medication Questionnaire, and
others.
Discussion
The use of chronic opioid therapy in patients with non-
malignant pain syndromes is controversial. Its long-
term efficacy is uncertain, and the benefits and harms
are often finely balanced. Risks of chronic opioid ther-
apy include the development of addiction or depen-
dence syndromes, opioid-induced hyperalgesia, and
the potential for diversion or misuse of prescribed
opioids. These problems have received a great deal of
attention from the popular media, politicians, and reg-
ulators. For all of these reasons, patients on chronic
opioid therapy must be closely monitored, with regu-
lar office visits and efforts to minimize the misuse or
diversion of such drugs.
Urine or blood drug testing is nearly always an
important part of a monitoring plan for patients on
opioid maintenance therapy. In most cases, we recom-
mend a baseline urine drug test before starting therapy,
as well as regular random tests. The frequency of such
testing depends on the patient’s circumstances. In gen-
eral, high-risk patients should be monitored more fre-
quently, possibly at every visit. For long-term patients
who appear to be stable and at low risk of diver-
sion or misuse, we still recommend random testing
once or twice a year. One study of headache patients
receiving opioid maintenance therapy showed that
77
 Chapter 5: Blood, urine, and other tests
unexpected urine drug test results suggesting aberrant
drug-related behavior occurred in a sizeable propor-
tion of apparently stable patients, sometimes even after
long periods of trouble-free use.
Patients can be referred to independent laborato-
ries for such testing, but many physicians obtain the
urine samples in their own offices. These samples are
not usually handled with the same strict “chain of cus-
tody” procedures applied in professional laboratories.
Diagnosis
Post-traumatic head and facial pain, treated with
chronic opioid therapy.
Tip
Urine or blood drug testing does not reliably detect
some opioids, such as fentanyl, but such tests are still
valuable to detect use of other nonprescribed sub-
stances. Knowledge of cross-reactive substances that
can produce false-positive urine drug tests is impor-
tant to avoid inaccurately accusing patients of non-
compliance with treatment standards.
Lithium levels in a patient with
cluster headache
Case
A 45-year-old man presented to the headache clinic
with a ten-year history of right retro-orbital attacks of
10/10 pain. These lasted 45 minutes to an hour and
were associated with right-sided ptosis, rhinorrhea,
and tearing of the right eye. During attacks the patient
was restless and sometimes banged his head on the
wall. Initially these attacks occurred infrequently and
he was diagnosed with a possible sinus problem. He
underwent sinus surgery with no improvement, and
attacks began to increase in frequency. He was referred
to a neurologist who diagnosed cluster headache and
treated him with verapamil after he failed to respond to
a course of oral steroid therapy. Over the last year and
a half, the headache attacks had become daily despite
continued treatment with verapamil, which had been
increased to 320 mg/day. The patient was also using
oral zolmitriptan and hydrocodone to treat individual
attacks of headache, but reported they were not always
effective.
78
The headache specialist obtained an electrocardio-
gram, which showed a PR interval of 0.2 seconds. She
asked the patient to decrease his verapamil dose to
240 mg/day, and suggested that he add lithium car-
bonate, 300 mg twice a day, to his treatment regi-
men. She also recommended subcutaneous sumatrip-
tan in place of oral zolmitriptan to treat individual
attacks of headache. She asked the patient to return a
week later to have his lithium level and an electrocar-
diogram checked. The electrocardiogram showed the
PR interval had returned to normal, but the patient’s
lithium level was low at 0.3 mmol/L (normal range
for this laboratory was 0.5–1.3 mmol/L). The doc-
tor asked the patient to increase his lithium dose to
300 mg of lithium carbonate three times daily. When
checked a month later, his lithium level was still low at
0.3 mmol/L and his headaches were no better. The doc-
tor increased the lithium dose again, but a week later a
third lithium level was 0.2 mmol/L.
What are the possible explanations for this
patient’s lithium level?
This patient’s lithium level was low when he began
taking lithium and remained essentially unchanged
despite two increases in the prescribed dose of lithium.
It is unlikely that these multiple test results were
incorrect. Although lithium can interact with a num-
ber of medications, this patient’s medication regimen
was otherwise unchanged during the period when his
lithium dosage had been increased. Thus, the most
likely explanation for these consistently low levels was
that the patient was nonadherent with the prescribed
dose of lithium.
There are many reasons for nonadherence to drug
therapy, which are discussed below. In this case, the
patient’s physician approached the matter in a non-
judgmental way, since she knew that patients are often
reluctant to admit they have not adhered to ther-
apeutic recommendations. She told the patient that
his lithium level had remained unchanged despite the
recommended increases in dose; she then “normal-
ized” the behavior of nonadherence by remarking that
“many patients find it difficult to take their medicine
regularly” and asking the patient if that was true for
him. The patient appeared relieved and responded that
his busy workday made it difficult to remember his
morning dose of medication, and that he sometimes

forgot to take his evening dose because of the demands
of his three children when he returned home at night.
The patient and physician then strategized about
ways in which he might remember to take his medica-
tion, and the patient decided to program an alarm on
his cellphone. The doctor also reviewed the expected
benefits of lithium and the fact that alternative treat-
ments that might be used in its place had less evidence
of benefit. Both she and the patient were pleased when
at his next visit his headaches were greatly diminished
and his lithium level had increased to 0.8 mmol/L.
How common is nonadherence to drug
therapy in headache patients and why does
it occur?
Nonadherence or poor compliance to recommended
treatment is an important problem with all types of
medical treatment, particularly with complex treat-
ment regimens for chronic illnesses. There is no evi-
dence that nonadherence is more common among
headache patients than the general medical popula-
tion. Failure to adhere to recommended treatment can
take the form of overuse of prescribed or over-the-
counter treatments, or underuse, which may consist of
never filling a prescription at all, using less than the
recommended dose, or premature cessation of treat-
ment. One study of headache patients found that only
slightly more than a third of patients were fully com-
pliant with their prescribed treatment regimens.
There are many reasons for nonadherence to pre-
scribed therapy. One study found that medication
costs, patient uncertainty that the drug was indicated,
or fears of side effects were the most common reasons
for nonadherence.
Poor adherence is also related to the complexity
of the treatment regimen. The more frequently a drug
must be taken, for example, the less likely patients are
to adhere to the regimen. When feasible, switching to
once-daily treatments can improve the likelihood of
adherence to drug regimens. Nonadherence to pre-
scribed medications is probably an underappreciated
reason for the apparent failure of headache treatment
regimens. In the case described in this vignette, the
patient happened to be taking one of the few headache
drugs that require monitoring of serum drug levels.
If blood tests had not been obtained, it is likely that
his nonadherence would have gone undetected and
Chapter 5: Blood, urine, and other tests
lithium would have been inaccurately regarded as inef-
fective for his cluster headache.
Discussion
The FDA has not approved any drugs for preven-
tive treatment of cluster headache, but verapamil and
lithium are widely used off-label. Verapamil is the pre-
ferred initial drug because it seems to have a quicker
onset of action and fewer side effects. Lithium is used
alone when verapamil is ineffective or not tolerated, or
as an add-on to verapamil when combination therapy
is needed. The scientific evidence supporting its use is
modest, but clinically it is perceived to be quite effec-
tive, particularly in chronic cluster headache. A typi-
cal starting dose is 300 mg of lithium carbonate given
twice a day, which can be increased in 300 mg incre-
ments based on treatment response and blood levels.
Most patients who respond to the drug do so at doses
between 600 and 1200 mg/day.
Nuisance side effects such as tremor, nausea, or
diarrhea are relatively common, and at higher doses
lithium toxicity can occur. This can produce kidney
dysfunction, ataxia, or convulsions that may be fatal.
Sodium depletion, which can occur with the use of
some diuretics, may increase the likelihood of lithium
toxicity. Nonsteroidal anti-inflammatory medications
may increase lithium levels. Verapamil has been
reported both to increase and decrease lithium levels.
Because lithium has a narrow therapeutic win-
dow, periodic monitoring of blood levels is necessary
to avoid toxicity. Levels should be checked after any
dosage increase, when symptoms related to toxicity
occur, or when other medications that might affect
lithium levels are started or stopped. Blood levels do
not, however, correlate with response to the drug, so
there is no “target” blood level. In patients on long-
term lithium therapy most physicians also check yearly
kidney function and thyroid function tests.
Diagnosis
Chronic cluster headache with nonadherence to
lithium treatment.
Tip
Blood levels should be periodically monitored in
patients taking lithium. Although principally intended
to avoid toxicity, blood levels may also be used to assess
adherence to the prescribed treatment regimen.
79
 Chapter 5: Blood, urine, and other tests
A young man with body aches, rash,
and headache
Case
A 24-year-old man sought treatment in the emergency
department for a chronic headache. He described
the headache as dull and generalized. He also com-
plained of body aches and sensitivity to light. He
was afebrile and his physical examination was nor-
mal with the exception of a macular red rash over the
torso and some cervical lymphadenopathy. The emer-
gency department physician made a diagnosis of pos-
sible mononucleosis and sent the patient home with
instructions to see his primary care physician if the
symptoms did not remit.
A week later the patient saw his primary care doc-
tor because of continued headache and body aches.
The doctor asked the patient whether he had other
reasons for seeking treatment and what he thought
might be the cause of his problems. The patient con-
fided that his new girlfriend had been an intravenous
drug abuser; over the last few months they had had
many unsafe sexual encounters and he worried that
he might have “some kind of infection.” The physi-
cian recognized that the patient was at high risk for a
variety of sexually transmitted infections and ordered
appropriate testing, including an HIV antibody test
and an HIV RNA (viral load) test. The HIV anti-
body test was positive and the patient’s viral load was
⬎ 100 000 copies/mL.
Can headache be a symptom of
HIV infection?
This case is a reminder that a half to two-thirds of peo-
ple with newly acquired HIV infection will experience
a constellation of signs and symptoms as they sero-
convert, usually about two to eight weeks following
infection. Headache may be a prominent symptom of
this influenza-like event, which is often termed “acute
retroviral syndrome” and lasts an average of about a
month. In one series of 218 patients with acute HIV
infection, headache was reported by 51%. Only fever
(77%), lethargy (66%), and skin rash (56%) were more
common. Other neurologic symptoms of photophobia
and meningismus (stiff neck) were reported by 12%
and 9% of patients, respectively, making headache by
far the most common neurologic symptom of acute
80
HIV infection. In our experience, such patients do
not usually come to the headache clinic but are more
likely to present in an emergency department or urgent
care setting, given the abrupt nature and relatively
short duration of symptoms. The reason for headache
or other symptoms is not fully understood, but may
involve release of cytokines.
A more chronic form of headache has been
described in people with stable HIV infection. Once
superimposed infections related to immunosuppres-
sion have been eliminated as a cause of headache, a
diagnosis of headache attributed to human immuno-
deficiency syndrome/acquired immunodeficiency
syndrome (HIV/AIDS) can be considered. This diag-
nosis is contained in the appendix of ICHD-3 beta
rather than the main body of the classification because
the validity of the diagnostic criteria has not been
firmly established. This is largely due to the fact that it
can be very challenging to distinguish the low-grade
headache likely to be attributable to HIV from other
forms of primary headache commonly reported by
HIV patients. Additionally, some antiretroviral drugs
can produce headache.
Nonetheless, most experts believe that low-grade
headache is a common feature of HIV infection. It
is typically a dull, bilateral headache. This diagno-
sis should only be made after blood testing confirms
infection with HIV and/or immunodeficiency, in con-
junction with demonstration of disease-related patho-
physiology “likely to cause headache.” Blood or oral
fluid samples can be tested with rapid tests but any
positive results require confirmation using immuno-
assay procedures. Because antibody tests may be nega-
tive early in the infectious process, an HIV RNA (viral
load) test should also be ordered in settings where
infection may have been recent.
What are some other possible causes of
headache in people with HIV infection?
A high index of suspicion for secondary causes of
headache is appropriate in HIV-positive patients, par-
ticularly when immunosuppression is severe. A large
number of opportunistic infections such as Crypto-
coccus or toxoplasmosis can produce headache, and
patients with HIV also have an increased risk of central
nervous system neoplasms.
The degree of immunosuppression is positively
correlated with the likelihood of these secondary
 Chapter 5: Blood, urine, and other tests

causes of headache, and can be useful in deciding illness who have risk factors for sexually transmitted
whether or not an HIV-positive patient with headache diseases. To maximize the chance of detecting recent
needs a brain scan. One study found that impor- infection, both an HIV antibody test and an HIV RNA
tant abnormalities on CT scans of the brain were far (viral load) test should be ordered.
more likely in patients whose CD4 counts were below
200 cells/␮L, and recommended this as a threshold
below which imaging should be considered.
A young woman with headache and
multiple laboratory abnormalities
Discussion Case
A high degree of suspicion should be maintained for
A 19-year-old woman was seen in the headache clinic
the possibility of acute HIV infection in people with
on referral from her primary care physician. She
headache and risk factors for sexually transmitted dis-
had developed headaches a few months earlier. These
eases. Individuals with acute HIV infection may have
occurred on average twice a month and were very
very high viral loads and be particularly infectious
severe. She described them as pounding and usually
to others. Following the period of symptoms during
located over her right temple. These headaches could
seroconversion, infected people may experience a long
last up to two days at a time and were associated with
interval during which they have relatively few signs
severe nausea and vomiting and sensitivity to noise.
or symptoms, and diagnosis may be delayed. Thus the
She was unable to function during the headaches and
correct recognition of the acute retroviral syndrome
retreated to her darkened bedroom, although between
may allow early diagnosis of a potentially fatal illness
headaches she was active and well.
and the opportunity to minimize the risk of transmis-
The patient’s primary care physician thought that
sion to others. Unfortunately, because the symptoms of
migraine was the most likely diagnosis. However, the
acute retroviral syndrome are variable and nonspecific,
patient’s parents were very concerned and insisted on
this opportunity is often missed.
a “complete workup” to rule out dangerous causes of
In the case described in the vignette, the emer-
headache. A CT scan of the brain was normal. A large
gency department physician missed an opportunity to
number of blood tests had also been ordered, and sev-
identify the patient’s HIV infection, but fortunately
eral of these had been abnormal. Her antinuclear anti-
the patient again sought treatment. His primary care
body (ANA) test was positive at 1:80 so the patient
physician correctly recognized that the patient had risk
had been seen by a rheumatology consultant, who after
factors for HIV infection through his exposure to a for-
extensive further testing did not find evidence that the
mer intravenous drug abuser. The prevalence of HIV is
patient had systemic lupus erythematosus (SLE) or any
high in intravenous drug users, and their sexual part-
other rheumatic disease. Her thyroid-stimulating hor-
ners are at risk of infection with this and other blood-
mone (TSH) level was also slightly elevated, and the
borne infections such as hepatitis. A recent study sug-
patient had been seen by an endocrinologist who, after
gests that a short course of antiretroviral treatment
further testing, did not find any evidence of thyroid
early in HIV infection may delay disease progression,
dysfunction, but did note a small 1 cm thyroid nodule,
with important benefits for individual patients and
which proved to be benign on fine-needle aspiration.
public health, making it even more important to detect
infection as early as possible.
Was it a mistake to order all of these tests?
Diagnosis In a word, yes. Laboratory testing should be limited to
Headache related to acute retroviral syndrome (HIV patients who have a reasonable pre-test probability of
seroconversion). the disease the test is meant to detect. The physician
in this case meant well, but both he and the patient’s
parents failed to appreciate one of the common pitfalls
Tip of diagnostic testing, which is that testing should be
Acute retroviral syndrome should be considered in ordered based on the clinical context. In trying to
patients presenting with headache and influenza-like make sense of this concept, it is helpful to understand

81
 Chapter 5: Blood, urine, and other tests
the concepts of sensitivity, specificity, and positive
and negative predictive values. Together, these are
the operating characteristics of a test. Sensitivity is the
proportion of patients with a disease who have a pos-
itive test result. Specificity is the proportion of patients
without a disease who have a negative test result. The
predictive value of a test is the likelihood that a patient
does or does not have a disease given a particular
test result. Positive predictive value is the likelihood
that a patient with a positive test result really has the
disease in question, and negative predictive value is
the likelihood that a patient with a negative test result
really is disease-free.
The sensitivity and specificity of a test do not vary
from patient to patient, but the positive and nega-
tive predictive values of a test can differ dramatically
depending on the prevalence of the disease in the
population that is being tested. In the patient in the
vignette, the likelihood that she had lupus was low –
for the purposes of demonstration, let’s assume it was
on the order of 1%. In other words, assume that in
100 otherwise healthy young women like our patient
who have intermittent severe headaches, one truly has
SLE. If an ANA test for SLE has a sensitivity of 100%
and a specificity of 90%, the positive predictive value
of the test is only 9%. In other words, there was still
a 91% chance the patient did not have SLE even with
a positive test. (If you are interested in the details of
this calculation, positive predictive value is calculated
by dividing the true-positive rate by the true-positive
plus false-positive rate; in other words, 100%/[100% +
10%], which equals roughly 9%.) The bottom line is
that when the prior probability of disease is low, the
positive predictive value of a test is poor. Addition-
ally, when a large number of tests are ordered, some
are likely to be abnormal on the basis of chance alone.
Discussion
Laboratory and other tests are most helpful when
ordered based on the clinical context of an individual
patient’s situation. They should be ordered selectively
and interpreted very cautiously. It is difficult to defend
the practice of routinely ordering a large panel of tests
for all patients with a particular problem without con-
sideration of the individual clinical situation.
The incidence (new onset of disease) of migraine
is very high in young women, and this patient’s
headaches met criteria for that disorder. She was oth-
erwise healthy and her physical and neurologic exam-
82
inations were normal. Thus, the likelihood of a sinis-
ter cause of headache was very low. She had no other
signs or symptoms that might suggest thyroid abnor-
malities or an autoimmune disorder or any of the other
diseases for which she was tested. Specifically, she had
not experienced recent fatigue, constipation, skin rash,
or any other systemic indicators of underlying disease.
The extensive testing that was ordered was not done
because of any suspicion that a particular disease was
present, but rather to appease the patient’s parents and
ease their anxiety about a possible dangerous cause of
headache.
Although blood tests are not invasive and are com-
monly perceived as harmless, a good case can be made
that indiscriminate testing harmed the patient in this
vignette. Not only was attention to her presenting
problem – migraine – delayed by additional fruitless
investigation, she was exposed to radiation from a
CT scan of the head and underwent invasive aspira-
tion needle biopsy for an incidental thyroid nodule.
This sort of additional investigation triggered by an
abnormal finding is often referred to as the “medical
cascade.” Additional invasive diagnostic procedures
always carry a risk of harm, and certainly the wait for
results creates anxiety. These harms and the costs of
additional testing may be low for an individual patient,
but if such unnecessary testing occurs on a widespread
scale the iatrogenic harms and costs can be substantial
on a population level. Ordering a large number of tests
in the absence of specific indications for testing does
not represent high value medical care.
Patients (and sometimes physicians) commonly
overestimate the value of laboratory or other forms of
testing and have unrealistic ideas about the accuracy of
many tests. No test is perfect: not all positive or abnor-
mal test results indicate disease – instead, some are
false positives. Similarly, not all negative or normal test
results mean that a patient does not have the disease
in question – these are false negatives. In situations
where the likelihood of disease is low, as in the patient
in this vignette, positive results on a test are more likely
to be false positives than true indicators of disease. In
other words, their positive predictive value (the likeli-
hood that a patient with a positive test actually has the
disease in question) is low.
Diagnosis
Migraine and iatrogenic harm from unnecessary
testing.

Tip
A shotgun approach to testing in patients with
headache is inadvisable. In settings where the prior
probability of a particular disorder is low, most
abnormal test results will be false positives, evalua-
tion of which can lead to unnecessary anxiety and
possible harm from unneeded additional testing or
interventions – the so-called “medical cascade.”
Further reading
Menstrual migraine
Loder E, Rizzoli P, Golub J. Hormonal management of
migraine associated with menses and the menopause: a
clinical review. Headache. 2007;47(2):329–40.
Marcus DA, Bernstein CD, Sullivan EA, Rudy TE. A
prospective comparison between ICHD-II and
probability menstrual migraine diagnostic criteria.
Headache. 2010;50:539–50.
Somerville BW. The role of estradiol withdrawal in the
etiology of menstrual migraine. Neurology. 1972;
22(4):355–65.
Verapamil treatment of cluster headache
Cohen AS, Matharu MS, Goadsby PJ. Electrocardiographic
abnormalities in patients with cluster headache on
verapamil therapy. Neurology. 2007;69:668–75.
Leone M, D’Amico D, Frediani F, et al. Verapamil in the
prophylaxis of episodic cluster headache: a double-blind
study versus placebo. Neurology. 2000;54:1382–5.
Nesbitt AD, Goadsby PJ. Clinical review: cluster headache.
BMJ. 2012;344:e2407.
Chronic opioid therapy
Manchikanti L, Abdi S, Atluri S, et al. American Society of
Interventional Pain Physicians (ASIPP) guidelines for
responsible opioid prescribing in chronic non-cancer
pain, Parts 1 and 2. Pain Physician. 2012;15:S1–100.
Owen GT, Burton AW, Schade CM, Passik S. Urine drug
testing: current recommendations and best practices.
Pain Physician. 2012;15:ES119–33.
Lithium for cluster headache and nonadherence to
medication
Hedenrud T, Jonsson P, Linde M. Beliefs about medicines
and adherence among Swedish migraineurs. Ann
Pharmacother. 2007;42:39–45.
Chapter 5: Blood, urine, and other tests
May A, Leone M, Afra J, et al. EFNS guidelines on the
treatment of cluster headache and other trigeminal-
autonomic cephalalgias. Eur J Neurol. 2006;13:1066–
77.
Rains JC, Penzien DB, Lipchik GL. Behavioral facilitation of
medical treatment for headache – Part II: Theoretical
models and behavioral strategies for improving
adherence. Headache. 2006;46:1395–403.
Tfeldt-Hansen PC, Jensen RH. Management of cluster
headache. CNS Drugs. 2012;26(7):571–80.
Acute retroviral syndrome
Cohen HS, Gay CL, Busch MP, Hecht FM. The detection of
acute HIV infection. J Infect Dis. 2010;202(Suppl 2):
S270–7.
Graham CB, Wippold FJ, Pilgram TK, Fisher EJ, Smoker
WRK. Screening CT of the brain determined by CD4
count in HIV-positive patients presenting with
headache. AJNR Am J Neuroradiol. 2000;21:451–4.
The SPARTAC Trial Investigators. Short-course
antiretroviral therapy in primary HIV infection.
N Engl J Med. 2013;368:207–17.
Vanhems P, Allard R, Cooper DA, et al. Acute human
immunodeficiency virus type 1 disease as a
mononucleosis-like illness: is the diagnosis too
restrictive? Clin Infect Dis. 1997;24:965–70.
Vanhems P, Dassa C, Lambert J, et al. Comprehensive
classification of symptoms and signs reported among
218 patients with acute HIV-1 infection. J Acquir
Immune Defic Syndr. 1999;21:99–106.
Iatrogenic harms of unnecessary testing
Gough J, Scott-Coombes D, Palazzo FF. Thyroid
incidentaloma: an evidence-based assessment of
management strategy. World J Surg. 2008;32(7):
1264–8.
Loder E, Cardona L. Evaluation for secondary causes of
headache: the role of blood and urine testing. Headache.
2011;51:338–45.
Qaseem A, Alguire P, Dallas P, et al. Appropriate use of
screening and diagnostic tests to foster high-value,
cost-conscious care. Ann Intern Med. 2012;156(2):
147–9.
Ulvestad E, Kanestrøm A, Madland TM, et al. Evaluation
of diagnostic tests for antinuclear antibodies in
rheumatological practice. Scand J Immunol.
2000;52:309–15.
83
 Chapter
When historical or examination findings are
6 missed or misinterpreted
There are no biomarkers for benign headache disor-
ders such as migraine, and laboratory or imaging stud-
ies serve mainly to exclude other causes of headache.
Thorough patient evaluation, especially a careful his-
tory and physical examination, is therefore essen-
tial for the accurate diagnosis of headache problems.
Headache diagnosis has important treatment impli-
cations, since management that is effective for one
form of headache may be ineffective for another. Over-
looked or misinterpreted historical or examination
findings can result in missed diagnoses and lost oppor-
tunities for appropriate therapy. One common exam-
ple is a patient with cluster headache who has been
misdiagnosed with migraine and treated ineffectively
with anti-migraine drugs for years.
Most seasoned headache experts recognize that the
patient history is usually more informative than the
physical examination. In fact, the physical examina-
tion is expected to be normal in most patients with
primary headache disorders. Despite this, additional
findings such as occipito-nuchal tenderness, abnormal
neck posture, or temporomandibular joint dysfunc-
tion can identify problems that might be contribut-
ing to a primary headache disorder. Documentation
of these findings also can be helpful to patients for
insurance reasons or disability determination. The fact
that physical or neurologic abnormalities are uncom-
monly encountered in headache patients may lull doc-
tors into a false sense of security. Thorough examina-
tion of all patients with headache is important since,
as cases in this chapter illustrate, subtle findings can
change a diagnosis and influence treatment.
Considerable skill is sometimes required to obtain
a thorough history of headache problems, especially
in cases of long-standing headache with many failed
treatment attempts. We find it helpful to begin with the
open-ended question “Tell me about your headaches.”
This allows the patient uninterrupted time to tell
their story. The resulting narrative is often therapeu-
84
tic for the patient and instructive for the physician.
Many patients will spontaneously describe features
such as photophobia or vomiting that are required for
headache diagnosis; the physician can query missing
information later.
It is important to note that although most patients
should be allowed to tell their story in an unfettered
way, some patients may require different degrees of
active guidance from the provider. This can help retain
a focus on the most salient details, the result being a
narrative crafted from a balance of conversational flow
and what could be termed “supportive” redirection on
the part of the provider: for example, “Let’s put your
visit to the emergency department aside for now and
go back to what you were saying about your headache.”
With only some practice and without any special
or expensive technology, the provider can, after an
effective history and physical examination, expect to
arrive at a correct headache diagnosis much of the
time. When the process breaks down or shortcuts are
taken, various complications can occur, as illustrated
by the following cases.
A young man with visual changes and
a sore head
Case
A 28-year-old man with a prior history of hypertension
was seen in the emergency department with a com-
plaint of sudden visual changes. The patient described
a “flashing” in his peripheral vision that started in one
eye and spread to both over a period of about ten min-
utes. This gradually evolved into what he described as
a “flashing floater” along the edges of his vision bilat-
erally. This was followed by blurred vision in the orig-
inally affected eye.
The visual symptoms, which had lasted a total of
20 minutes, gradually disappeared while the patient
 Chapter 6: Missed historical features

Table 6.1. Features suggestive of retinal detachment Table 6.2. Selected features that distinguish the visual aura of
migraine from ischemic events
Acute visual loss (this is an ophthalmologic emergency)
Visual aura of migraine Ischemic events
Recent onset of visual “floaters”
Visual phenomena begin in Sudden onset of visual loss
Sudden onset of flashes of light
the periphery and develop
Darkening of vision or development of a curtain or shadow gradually
across vision
Both positive and negative Negative visual symptoms
visual phenomena are present predominate
Reversible, with duration of Short duration (typically no
event no longer than an hour more than 15 minutes)
was on the way to the emergency department. There
was no associated headache. The emergency depart- If other aura symptoms are If other neurologic symptoms
present, they occur in are present, they occur
ment physicians were concerned about the possibil- sequence simultaneously with visual
ity of a transient ischemic attack and he underwent phenomena
an evaluation that included a carotid ultrasound, a CT Similar events on multiple No prior history of similar
scan of his head, and consultation by an ophthalmol- occasions events
ogy resident. The results of these investigations were Symptoms are followed by Headache is not a common
normal and he was discharged home with instructions headache (usually within associated feature
15 minutes)
to take 81 mg of aspirin daily and follow up in the out-
patient neurology clinic.
He was seen in the clinic several days later where
a neurologist elicited a history of several similar sient ischemic attacks from more benign causes of
episodes of visual disturbance when the patient was in visual symptoms such as migraine aura, but several
his teens. Those were described as periods of “fluttery” historical features, which are listed in Table 6.2, can
peripheral vision lasting 5–25 minutes and followed by help.
a period of mild head “soreness.” These episodes had The patient described in the case experienced a
occurred sporadically over a period of several years mixture of positive and negative visual features that
and then disappeared. The patient had sought ophthal- developed gradually and were followed by headache.
mologic examination at the time but no abnormalities These are all more characteristic of visual aura than of
were found. transient ischemic attack. Patients often find it difficult
to describe visual aura. Obtaining a previous history
of such attacks can be very helpful. We make a spe-
What is the differential diagnosis of these cial point of inquiring about such attacks at a younger
visual symptoms? age, since in our experience patients may not sponta-
Isolated visual symptoms can be related to intraoc- neously report them.
ular pathology, transient ischemic attacks, migraine
aura, retinal detachment, or seizures. Visual phenom- What bedside test may have helped clarify
ena are often described as “positive” or “negative.” Pos-
itive visual phenomena include false visual images or the diagnosis?
distortions of normal vision, such as sparkling lights, Almost all patients who have any type of migraine
lines, or geometric shapes, spots of color, or shimmer- aura also have visual aura. Thus, in order to recog-
ing vision. Negative visual phenomena, on the other nize patients with aura, it is only necessary to establish
hand, include visual deficits such as dark or blind the presence of visual aura. This can be done using the
spots. Visual Aura Rating Scale (VARS), which is a validated
The differential diagnosis for visual symptoms tool developed for this purpose. The point system used
that resolve spontaneously includes seizures, migraine by the VARS is described in Table 6.3. The VARS is sim-
aura, and transient ischemic attacks. Symptoms that ple to administer at the bedside or in the office. Points
persist beyond an hour or two require urgent investiga- are assigned for the presence of any of five character-
tion for intraocular pathology such as retinal detach- istics of visual aura: duration from 5 to 60 minutes,
ment; features characteristic of this diagnosis are listed gradual onset, visual scotoma, zig-zag lines, or uni-
in Table 6.1. It can be difficult to distinguish tran- lateral location of the visual phenomena. The patient

85
 Chapter 6: Missed historical features
Table 6.3. The Visual Aura Rating Scale for the diagnosis of
migraine with aura
Feature
Duration 5–60 minutes
Develops gradually ࣙ 5 minutes
Presence of associated scotoma (blind spot)
Zig-zag lines (fortification spectra)
Unilateral location
A VARS score of 5 or more diagnosed migraine with aura with a
sensitivity of 96% (95% confidence interval [CI] 92–99%) and a
specificity of 98% (95% CI 95–100%).
Reproduced with permission from: Eriksen MK, Thomsen LL, Ole-
sen J. The Visual Aura Rating Scale (VARS) for migraine aura diag-
nosis. Cephalalgia. 2005;25(10):801–10.
described in this case would have scored five of ten
possible points. The use of the VARS or elicitation of
the history of similar episodes when he was younger
might have spared him an unnecessary workup for
transient ischemic attack, and unnecessary treatment
with aspirin. In the past, some physicians prescribed
low-dose aspirin therapy for patients with aura, but
there is no evidence that this is beneficial, and some
recent evidence suggests it may be harmful. Thus, we
do not recommend the use of low-dose aspirin therapy
in patients with migraine aura.
Discussion
Aura occurs in about a third of patients with migraine.
Visual aura is by far the most common type of aura,
occurring in 99% of subjects with aura. This is fol-
lowed by sensory aura (31%) and aura involving lan-
guage symptoms such as aphasia (18%). Motor aura is
rare, and this special form of aura is separately recog-
nized as hemiplegic migraine. Some forms of hemi-
plegic migraine are autosomal dominant single gene
disorders; these have provided an important opportu-
nity to study the genetics of migraine.
Migraine aura is thought to be due to the phe-
nomenon of cortical spreading depression, which is an
orderly wave of depolarization that spreads anteriorly
across the cerebral cortex. This is followed by a pro-
longed period during which neurons struggle to repo-
larize (hence the term “depression”) and is followed
by a small reduction in regional cerebral blood flow.
The wave of neuronal depolarization spreads at a rate
of 2–5 mm per minute, which correlates closely with
86
Table 6.4. Clinical characteristics of aura
One of the following features should be present:
Points 1. Fully reversible (usually homonymous) visual symptoms
including positive features (e.g. flickering lights, spots, or lines)
3 points
and/or negative features (e.g. loss of vision)
2 points 2. Fully reversible (usually unilateral) sensory symptoms including
positive features (e.g. pins and needles) and/or negative
2 points features (e.g. numbness)
2 points 3. Fully reversible dysphasic speech disturbance
1 point
the evolution of visual or sensory symptoms during an
aura.
Aura symptoms usually develop gradually over five
or more minutes, and different aura symptoms, when
present, usually develop in succession, each lasting
between 5 and 60 minutes. Associated loss of vision
or blurred vision may be present, but blurred vision
alone is not sufficient to make a diagnosis of visual
aura. Table 6.4 lists the typical features of aura.
Aura may occur without a subsequent headache or
can be followed by a mild, non-migrainous headache.
With age, patients may lose characteristic migraine
headache features or may not experience headache at
all after an aura. The diagnosis of visual aura with-
out headache thus occurs more frequently in older
patients.
Diagnosis
Typical aura with headache.
Tip
Failure to elicit historical features consistent with
migraine aura can lead to an erroneous diagnosis of
cerebral ischemia in patients with aura.
A young woman with a headache that
was “worse than ever”
Case
A 30-year-old obese female presented to a headache
clinic with records from her initial evaluation at
another clinic for the same symptoms. These records
indicated that she had initially reported several
months of a “worse than ever” daily headache
sometimes associated with “black spots” in her
vision, nausea, vomiting, and photo and phonopho-
bia. She was taking a combination estrogen–progestin

contraceptive pill, and was a smoker. Her examination
was normal. The physician, hearing that she was hav-
ing “the worst headache ever,” was concerned about
a secondary headache. He sent her for an emergent
MRI followed by an unsuccessful attempt at lumbar
puncture. A second lumbar puncture was attempted
under fluoroscopy and was finally successful. This was
followed by an MRV. The results of these tests were
normal.
Was the physician’s level of concern
appropriate?
The phrase “worst headache ever” was understandably
worrying to this patient’s doctor, who undoubtedly was
concerned about secondary causes of headache such as
cerebral venous thrombosis or stroke. However, when
viewed in the context of the patient’s history this sit-
uation is not so alarming. In the headache clinic, the
patient was asked to provide a chronologic history that
included childhood headache symptoms and the evo-
lution of her headaches from onset to their current pat-
tern. This revealed a strong family history of migraine,
and a personal history of years of episodic migraine
headache with a gradual transformation to a chronic
situation.
This pattern is very typical of the evolution of
episodic to chronic migraine, caught around the time
of transformation of the headache pattern. Further-
more, the patient’s sex and obesity are factors asso-
ciated with an increased risk of transformation from
episodic to chronic migraine. When this patient’s
headache history is considered as a whole, the exten-
sive diagnostic workup that was undertaken seems
superfluous, costly, and unnecessarily invasive.
Two evaluations of the same historical
information produced divergent outcomes.
What went wrong?
The initial examiner failed to take into account the
context into which the current headache situation
fits. This is another example of the cognitive error
of premature closure. The doctor settled on a likely
diagnosis of a dangerous secondary headache based
on some details but minus other useful information.
This does not mean that his concern was completely
Chapter 6: Missed historical features
unfounded: certainly the patient’s nicotine addiction
deserves attention.
The picture that emerged of this patient’s
headaches appeared very different when consid-
ered in the overall context of her headaches. She
reported childhood carsickness and subsequent onset
of headaches with migrainous features in her 20s.
These headaches slowly progressed in frequency and
severity over many years. The change in her headache
pattern in the preceding four months before the cur-
rent evaluation was probably the point at which the
patient recognized that her headaches were becom-
ing chronic and more disabling. Because the initial
headache history did not elicit this story of gradual
progression, unnecessary diagnostic testing and treat-
ment ensued. Unnecessary diagnostic investigation is
often uncomfortable for the patient, provokes anxiety,
and creates the potential for iatrogenesis.
Discussion
In most cases the patient history is the most impor-
tant part of headache evaluation and sets the stage
for decision-making about testing and treatment. Con-
ventional teaching is that the patient history is a step-
wise process that begins with the history of the present
illness, proceeds through a review of what brought
the patient in for evaluation at that moment (the
chief complaint), and then the details of the current
problem.
In the evaluation of headache, however, it is often
wise to begin with an open-ended question such as
“tell me about your headaches” and then fill in details
using a time-based or chronologic approach. This
begins with questions about family history and child-
hood headache symptoms, followed by detailed lon-
gitudinal questioning about migraine-related symp-
toms during the teenage years and then in each decade
beyond the teens, with appropriate attention devoted
to headache changes associated with such events as
menarche, pregnancy, marriage, or job changes. The
headache history can then be considered in the context
of the overall history of headaches, which provides a
more complete picture and is likely to produce a more
accurate diagnosis.
Diagnosis
Migraine without aura, with transformation to chronic
migraine.
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 Chapter 6: Missed historical features
Tip
Failure to consider a patient’s current headache prob-
lem in the context of the overall headache history can
lead to unnecessary testing and treatment.
Intractable headache and psychiatric
illness in a young woman
Case
A 24-year-old female had been followed in adult neu-
rology since age 16, and before that in a pediatric neu-
rology clinic, for debilitating and limiting headache
associated with multiple psychiatric comorbidities.
Over the span of eight years, five neurologists had eval-
uated her for her headaches. She was also receiving
treatment from a psychiatrist and psychologist for anx-
iety, major depression, and suicidal gestures. She had
been hospitalized twice for management of psychiatric
problems, and had periodically been unable to attend
school for weeks at a time. Both her headaches and her
psychiatric problems had not improved despite multi-
ple trials of treatment.
When seen at her most recent visit, the patient told
her neurologist that she had read a magazine article
about the possible connection between headaches and
abuse. She told the doctor that she had been sexually
abused as a child by a relative. She said she had just
mentioned this to her therapist and was beginning to
explore the issue. A recent psychiatry chart note con-
firmed that the abuse history had “been revealed for
the first time.” Review of the patient’s record showed
no documentation of any previous questions or dis-
cussions about physical, emotional, or sexual abuse or
trauma, with the exception of a note in the psychiatry
intake form that stated: “Not evaluated at this time.”
Should the patient’s doctors have suspected
a prior history of abuse or trauma?
This patient’s doctors probably should have been more
alert to the possibility that this patient had experienced
prior maltreatment, since a history of abuse is very
common in patients with refractory headache disor-
ders. Traumatic experiences in childhood are linked
with an elevated risk of a large number of child-
hood and adult medical problems, including headache.
Trauma can result not only from the personal expe-
rience of violence or abuse, but also from witnessing
88
Table 6.5. Types of adverse or traumatic experiences
Physical abuse or neglect
Sexual abuse
Intimate partner violence
Emotional abuse or neglect
Alcohol or drug abuser in the home
No parents in the home or single parent
Chronically physically or mentally ill person in the home
Witnessing violence in the home or social environment
such events. Table 6.5 lists some common forms of
adverse or traumatic experiences. The prevalence of
childhood sexual or physical abuse or neglect is high in
the general population and is not confined to a particu-
lar ethnic or socioeconomic group. For example, some
sources estimate that as many as one in four girls and
one in six boys experience sexual abuse in childhood.
Abuse is not confined to children, however. Intimate
partner violence or other traumatic events frequently
occur in adulthood, and those with a childhood his-
tory of adverse experiences may be at high risk for later
revictimization.
The prevalence of abuse or trauma is even higher
in patients with chronic headache disorders than in
the general population. A large multicenter study
performed in specialty headache clinics found that
roughly a quarter of patients with migraine acknowl-
edged a history of physical or sexual abuse or neglect,
and over a third reported a history of emotional abuse
or neglect. There was substantial overlap of the differ-
ent forms of maltreatment, and almost half of those
who experienced abuse in childhood reported experi-
encing abuse in adulthood.
In our experience, it is prudent to maintain a
high index of suspicion about abuse or trauma in
patients with difficult-to-treat headaches. This patient
had intractable, debilitating headaches from a young
age, associated with severe, difficult to treat psychiatric
disease.
It is difficult to prove a causal relationship between
maltreatment and headache occurrence or intractabil-
ity, but several lines of evidence suggest this connec-
tion. For example, several studies have demonstrated
a dose–response relationship between the number of
adverse childhood experiences and the prevalence and
risk of frequent headaches in both sexes. Some evi-
dence suggests that childhood trauma can produce
permanent changes in the hypothalamic–pituitary

axis, while other work implicates the development of
poor coping strategies, somatization, or dissociation.
How and when should questions about
abuse or trauma be asked?
Good quality evidence supports an association
between maltreatment and chronic headache, but
there is no consensus about whether all patients
should be questioned about a history of abuse. At
present recommendations for screening are limited
to particular subgroups. For example, the United
States Preventive Services Task Force (USPSTF) has
reviewed available evidence and recommends that
“clinicians screen women of childbearing age for
intimate partner violence, such as domestic violence,
and provide or refer women who screen positive
to intervention services . . . The USPSTF concludes
that the current evidence is insufficient to assess
the balance of benefits and harms of screening all
elderly or vulnerable adults (physically or mentally
dysfunctional) for abuse and neglect.”
This patient was prompted to tell her caregivers
about a previous history of childhood sexual abuse
after reading about its possible connection with
chronic headaches. Her providers were distressed to
find that this history had remained undocumented for
so long. Few patients are likely to be as forthcoming
as this patient was. Our belief is that it makes sense to
ask about abuse routinely in patients seeking treatment
for headache problems, especially those whose prob-
lems have resisted treatment or occur in the context of
other psychiatric disorders. Psychiatrists often include
a history of abuse in their patient evaluations, but as
this case illustrates, this cannot be assumed.
There are several ways in which information about
maltreatment can be obtained. If patients are asked to
fill out written surveys or questionnaires prior to being
seen, the question can be asked in writing. Validated
instruments such as the Childhood Trauma Question-
naire can be used. In our practice we include a writ-
ten question about a history of trauma or abuse in the
information we ask patients to complete before being
seen. However, since patients may be reluctant to dis-
close this information on a form we also follow up with
a routine question during our initial meeting with the
patient.
We usually ask these questions when inquiring
about other aspects of the social history, first asking
patients about their living situation, and then moving
Chapter 6: Missed historical features
on to whether they feel safe in their current living sit-
uation, finally asking whether they have ever been in
a situation that was unsafe or abusive. As with other
sensitive information, it is helpful to frame the ques-
tions carefully. We try to “normalize” the disclosure of
such information by telling patients that many people
with chronic headache have experienced prior sexual
or physical abuse or trauma. We then let them know
that we routinely ask all patients about abuse, and fin-
ish with more specific questions.
How should doctors respond when patients
disclose abuse or trauma?
Most physicians are subject to mandatory report-
ing requirements if abuse is suspected in vulnerable
patients such as minor children or the elderly, and
some states have additional reporting requirements.
These vary and physicians are encouraged to stay up
to date with local regulations. In the case of competent
adult patients without immediate injuries, the physi-
cian usually is legally obligated to respect the privacy
of information disclosed in the doctor–patient rela-
tionship. The clinician’s role in these cases is limited to
helping the patient make decisions and ensuring they
have access to information about available help and
resources.
We tell adult patients who disclose abuse or trauma
that we are glad they told us about the maltreatment.
It is also important to tell the patient that “you do not
deserve to be treated like this.” The next step is to eval-
uate the immediate safety of patients who are currently
involved in abusive situations, and to give the patient
information about resources such as abuse hotlines,
legal resources, and healthcare resources. We keep a
variety of information pamphlets on hand for this
purpose.
In the case of patients who are involved in abusive
relationships, many clinicians are tempted to advise
the patient to leave the relationship or ask them why
they put up with such treatment. Although well inten-
tioned, such questions or advice may imply that you
hold the patient responsible for the abusive situation.
In some cases, such advice if acted upon may put the
patient or any involved children in danger from the
abuser. It is important to respect the patient’s choices
about whether or when to end a relationship. We tell
patients experiencing abuse that we are very concerned
about their welfare, recommend that they contact local
89
 Chapter 6: Missed historical features
counseling resources, and urge them to make follow-
up appointments so that we can monitor the situation.
Discussion
Good quality evidence supports a link between var-
ious forms of childhood abuse (sexual, physical, or
emotional) and later life pain syndromes, including
migraine. One study found that a past history of emo-
tional abuse was almost four times more common
in patients, mostly female, with migraine. Migraine
patients with a past history of such “adverse childhood
experiences” may be more likely to experience not only
chronic migraine in later years but also depression and
anxiety. They may also be less compliant with treat-
ment or medical appointments, particularly if the sit-
uation at home remains chaotic.
Because this is a relatively new area of research,
there are no clear implications for patient management
when a history of abuse is uncovered. We find, how-
ever, that patients who have experienced intimate part-
ner or sexual violence may have difficulty with treat-
ments that remind them of the circumstances of any
abuse. For example, a female patient who has been sex-
ually abused by an older male may become anxious
during physical therapy or relaxation sessions with an
older male therapist.
It is not clear that the outcome of this patient’s care
would have been different if her abuse history had been
known. It does, however, seem evident that it is an
integral part of her medical and psychosocial history.
Knowledge of this part of the patient’s history might
have helped her caregivers to understand the patient’s
headaches in the context of her life experiences. It is
important not to underestimate the effect that trau-
matic life experiences can have on a patient’s headache
problems.
Diagnosis
Chronic migraine in a patient with a history of child-
hood sexual abuse.
Tip
Do not forget to ask all headache patients, especially
those with treatment-refractory headaches, about a
history of sexual, physical, or emotional abuse or
trauma. These high-yield historical questions can clar-
ify a complex situation.
90
A man with headache, neurologic
symptoms, and spinal fluid pleocytosis
Case
A 33-year-old male was seen in the emergency depart-
ment with headache and neurologic symptoms. There
was a past history of occasional episodic migraine but
the patient had not been troubled by migraines for
several years. He was otherwise healthy and taking
no medications. The patient had developed a constant
mild frontal headache three days prior to evaluation.
On the fourth day, he had noted migratory right-sided
numbness and paresthesias in the arm, leg, and face.
Shortly thereafter he was unable to speak for a short
time, and following that he developed a “worst ever”
headache with associated nausea and vomiting. This
prompted urgent evaluation including a plain CT scan
of the head followed by lumbar puncture, MRA, and
MRV. Test results were normal except for the find-
ing of elevated white blood cells (150 cells/␮L) in the
CSF, lymphocyte predominant. He was afebrile. He
was advised that the diagnosis was viral meningitis.
One week later he noted a return of the numb-
ness followed by a one-hour episode of confusion and
a moderately severe headache. He returned to the
emergency department where evaluation was again
normal apart from elevated white cells in the CSF
(450 cells/␮L) and a mildly elevated CSF protein at
113 mg/dL. The diagnosis at that point was possible
viral encephalitis. He was admitted to the hospital and
placed on seizure prophylaxis and antiviral agents.
Was a diagnosis of encephalitis appropriate
in this case?
At the initial presentation, viral meningitis was a rea-
sonable diagnosis, although the patient did not report
a full range of typical symptoms such as fever, stiff
neck, or other viral features (malaise, muscle aches,
etc.). Additionally, the patient had reported the most
severe headache of his life and there was no history
of prior headache or migraine. In this setting, a sec-
ondary headache of some kind was a leading diag-
nostic possibility. During his second presentation the
patient’s symptoms included confusion, which indi-
cates a process affecting either the brainstem or both
halves of the cortex. On the other hand, no localizing
neurologic findings were noted and imaging findings
remained normal. Although the patient appeared less

Table 6.6. Clinical characteristics of headache with neurologic
deficits and CSF lymphocytosis (HaNDL)
r Episodes of moderate headache occurring with or quickly
followed by transient neurologic deficits
r Episodes of headache and focal neurologic deficits recur over
a period of less than 3 months
r Lumbar puncture findings show cerebrospinal fluid
pleocytosis with lymphocytic predominance (⬎ 15 cells/␮L)
r CSF culture and neuroimaging findings are normal
ill than might be expected with encephalitis, an early
or incomplete encephalitic process was plausible and
management for this potentially severe condition was
reasonable.
The patient stayed in the hospital for several days.
He remained afebrile and looked well at the time of dis-
charge. However, he returned again to the emergency
department three days later with a similar presenta-
tion: headache, confusion, and paresthesias, though
now these were all milder than at the time of the ini-
tial presentation. He was afebrile, looked well, and had
a normal examination at this last emergency depart-
ment visit. He underwent a diagnostic workup similar
to his previous episodes and was again admitted to the
hospital.
What is the best diagnosis at this point?
The diagnostic possibilities in this case are becom-
ing clearer as a history emerges of repeated benign
episodes of headache and CSF abnormalities. This
patient presented with new-onset headache without
migrainous features, with mild reversible focal neu-
rologic deficits, and CSF lymphocytosis. Furthermore,
such episodes recurred. This is the classic description
of headache with neurologic deficits and CSF lympho-
cytosis (HaNDL), which was first described in 1981.
Features of the syndrome that are helpful for diagnos-
tic purposes include a finding of CSF lymphocytosis
along with negative cultures (Table 6.6).
Clinical mimics of this syndrome include migraine
aura, transient ischemic attacks or stroke, as well as
viral meningitis or encephalitis. In this case, there
were no migraine features to the headache and the
episodes were not stereotyped, as would be expected
in migraine aura. Although about a third of patients
with HaNDL have a history of migraine, the clinical
significance of this is uncertain because the prevalence
of migraine is so high in the general population.
Chapter 6: Missed historical features
In hindsight, what historical and
examination features might have
suggested this patient’s condition was
benign?
Although abrupt headaches in combination with focal
neurologic deficits may indicate a serious disorder,
they can also be due to benign, self-limited problems.
In this patient there were no signs of ischemia on
imaging and it would be unusual for repeated tran-
sient ischemic attacks to occur in an otherwise healthy
young man. Although CSF lymphocytosis was docu-
mented, there were no other signs of infection. The
patient continued to feel and act better than would be
expected if he had an ongoing encephalitic or ischemic
process. Additionally, he was completely well between
episodes and his spinal fluid cultures were negative,
lowering the likelihood of any ongoing infectious
process.
Although physicians worry about missing poten-
tially severe but treatable conditions, they also have
a duty to protect patients from unnecessary testing,
iatrogenesis, and undue anxiety. In this case, more
restraint in testing and treatment was probably war-
ranted when, despite the worrisome diagnoses under
consideration, the patient continued to look and do
well.
Discussion
HaNDL is a rare but well-described syndrome that
may be confused with meningoencephalitis or other
serious conditions. It is benign and usually resolves on
its own. There are several case reports of patients with
HaNDL who were suspected of having acute stroke and
treated with systemic thrombolysis. Failure to recog-
nize the characteristic historical and examination fea-
tures of this illness can thus have serious consequences.
In this case the patient was unnecessarily treated with
antiepileptic and antiviral therapies.
HaNDL was initially thought to represent a form
of migraine, but current thinking centers on the pos-
sibility of a post-viral syndrome. The reversible focal
deficits have been attributed to transient vasoconstric-
tion. Some authors report that steroid treatment can
be helpful, although there are no large-scale studies to
support this view. Catheter angiography may worsen
symptoms and should be avoided if this condition is
suspected.
91
 Chapter 6: Missed historical features
Diagnosis
Headache with neurologic deficits and CSF lymphocy-
tosis (HaNDL).
Tip
Prompt recognition of benign historical and examina-
tion findings can save patients from invasive and dan-
gerous treatments or multiple hospitalizations.
An elderly woman with giant cell
arteritis and persistent headache
on steroids
Case
A 73-year-old female presented for evaluation of a
mild to moderately severe headache of three months’
duration. She described an achy global headache asso-
ciated with mild photophobia, ear pain and nausea.
She did not have distended temporal arteries or any
head soreness. There were no constitutional or jaw
claudication symptoms. As part of her evaluation, an
erythrocyte sedimentation rate (ESR) and C-reactive
protein (CRP) were obtained. Both were moderately
elevated, and a subsequent temporal artery biopsy
reportedly showed giant cell arteritis.
Her headache initially improved on initial doses of
prednisone but later returned during the prednisone
taper. The physician attributed this worsened headache
to ongoing arteritis and recommended an increase in
the patient’s corticosteroid dose. At the patient’s next
visit she reported that this increased dose had not
improved her symptoms. The physician asked her to
give a more complete description of the headache. She
reported that the headache was absent on waking each
day, but would begin after becoming upright for 10–15
minutes and progress throughout the day to a severity
of 6 on a 0–10 pain scale. The headache was dull and
bilateral. Her MRI was reviewed and, although it had
originally been read as normal, showed subtle find-
ings consistent with low CSF volume. Her symptoms
improved with use of an abdominal binder when she
was upright and a regimen of daily caffeine tablets. She
was eventually sent for an epidural blood patch and her
headache cleared completely.
92
Was giant cell arteritis the best initial
explanation of the headache pattern?
Headache associated with giant cell arteritis has been
described as generalized and throbbing, intermittent
or constant; but it can also be nonspecific, as it was in
this case. Temporal artery tenderness and enlargement
may be found on physical examination. In this case, a
temporal artery biopsy was positive and the patient ini-
tially improved with corticosteroid treatment. When
her headache recurred, the physician assumed the
symptoms were due to the original diagnosis but failed
to consider other possible explanations for the contin-
ued headache. This is an example of “anchoring bias,”
in which new historical information is interpreted in
the light of an established diagnosis, without consid-
eration of other explanations. In hindsight, although
this patient certainly did have giant cell arteritis, it is
unclear how much of the initial headache report was
explained by the arteritis. It is plausible that the symp-
toms of low CSF volume prompted her initial evalua-
tion. The possibility that this patient had two causes of
headache was not considered until relatively late in her
course.
When should a diagnosis be reconsidered?
In our experience, headaches attributable to giant
cell arteritis typically improve promptly with corti-
costeroid treatment, although there are occasional
patients where headaches linger. Worsening of
headache is sometimes attributable to incomplete
treatment of the arteritis and an elevation in steroid
dose is a reasonable first step. However, failure to
respond as expected to treatment (in this case to an ele-
vation of the corticosteroid dose) should raise concern
about alternative or additional diagnostic possibilities.
As was done by the physician in this case, it is help-
ful in such situations to put aside assumptions and re-
evaluate the headache history from the beginning. It
can also be useful to discuss the case with a colleague,
since presenting a case to someone forces a reconsid-
eration of the entire clinical picture.
Discussion
The physician in this case initially did not recognize
that the historical evolution of the patient’s headache
deviated from the clinical course expected with her ini-
tial diagnosis. Upon revisiting the history, however, he

elicited important information about postural features
of headache. This eventually led to the diagnosis of an
additional cause of headache: low CSF pressure, pre-
sumably from a spontaneous leak.
It is important to be vigilant for giant cell arteri-
tis in older patients, since it is a medical emergency.
The clinical picture of giant cell arteritis can be highly
variable, and early treatment with corticosteroids may
prevent permanent visual loss. Thus, a low threshold
for biopsy and treatment is appropriate. It is useful to
remember, however, that corticosteroid treatment may
produce temporary improvement in a wide variety of
headache types, so response to steroid treatment is not
diagnostic.
Diagnosis
Giant cell arteritis; low CSF pressure headache.
Tip
Patients can have more than one cause of headache.
When patients do not respond as expected to treat-
ment, the history should be carefully reviewed for
overlooked clues.
A man with unilateral headache and
subtle eye findings
Case
A 62-year-old man was seen for evaluation of a
headache that had started about three weeks ago.
He had a prior history of occasional bilateral, mild
headaches that lasted a few hours at most, but this
headache was located behind the right eye and was
continuous since onset. The patient reported that the
headache began after he had been target shooting for
several hours. This required him to close his left eye
frequently and hold his neck in a particular posture.
The evening of target practice and for two days after,
the patient had experienced blurry vision. His vision
then normalized, but he developed a continuous dull
right retro-orbital headache that radiated to the angle
of his jaw on the right. He had photophobia and wore
sunglasses, but denied any associated features such as
nausea or vomiting. He mentioned that he felt as if he
had some grit or sand in his right eye. Based on the uni-
lateral location of the headache, the physician made a
Chapter 6: Missed historical features
diagnosis of hemicrania continua and recommended
treatment with indomethacin.
The physician performed a brief examination but
the patient declined to remove his sunglasses for a fun-
duscopic inspection. As the patient was about to leave,
however, the patient’s wife asked the doctor why her
husband was “squinting” and noted “It’s been like that
since the headache started.” Upon further examina-
tion, the patient was noted to have right-sided ptosis
and miosis, with warmer skin on the right side of his
forehead. Further examination revealed a suggestion
of a slight left-sided central facial palsy and mild left
upper extremity weakness.
What is the differential diagnosis, and what
tests should be performed next?
Autonomic features are frequent accompaniments of
many types of headache, most notably the trigemi-
nal autonomic cephalgias and hemicrania continua.
They can also be seen in migraine. Thus, the differen-
tial diagnosis of side-locked headache in association
with ipsilateral autonomic features includes benign
headaches such as cluster headache, hemicrania con-
tinua, or even migraine, but also dangerous conditions
such as giant cell arteritis, carotid dissection, or cervi-
cal facet disease.
Neuroimaging should be considered in all patients
with side-locked headaches, even when they appear
to meet criteria for a benign headache disorder. MRI
of the cervical spine and MRA of the extracranial
carotid circulation are indicated when there are abnor-
mal examination findings, as there were in this case. In
older patients an ESR and CRP should also be consid-
ered, since giant cell arteritis can present as a unilateral
headache.
This patient had a normal ESR and CRP, but MRA
showed dissection of the extracranial part of the right
internal carotid artery with significant stenosis. The
patient was treated with aspirin.
What is the cause of the physical
examination findings in this patient?
The combination of ptosis and miosis is character-
istic of Horner’s syndrome. A lesion of sympathetic
fibers that innervate the face and eye causes this
problem. Other findings in Horner’s syndrome may
include anhidrosis (decreased sweating) on the side
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 Chapter 6: Missed historical features
of the lesion. Flushing and conjunctival injection are
less frequent. First-order neurons from the poste-
rior hypothalamus travel to the upper cervical and
lower thoracic segments of the spinal cord, where
they synapse with second-order preganglionic neu-
rons. These travel over the apex of the lung, pass
around the subclavian artery, and finally end in the
superior cervical ganglion. Here they synapse with
third-order postganglionic neurons, some of which
travel with the internal carotid artery through the cav-
ernous sinus to innervate the pupil and muscles of the
eyelid, others of which travel with the external carotid
artery to the facial sweat glands.
Suspicion should be high that patients with new-
onset Horner’s syndrome and headache may have a
dangerous secondary explanation for their problems.
This is true even when, as in this case, the headaches
appear to meet criteria for a benign form of headache.
A Horner’s syndrome may occur from a lesion any-
where along the sympathetic pathway. If needed, spe-
cial pupillary testing can establish whether lesions are
pre- or postganglionic. One frequent cause that also
presents with head or neck pain is carotid dissec-
tion. As described above, the sympathetic fibers lie
just outside the carotid artery and a dissection may
cause stretching of the fibers sufficient to disrupt func-
tioning. For this reason, a patient who presents with
headache and a Horner’s syndrome, or neck pain and
a Horner’s syndrome, should be evaluated with carotid
imaging. This could be accomplished with duplex
sonography, a CTA of the neck, or an MRA with fat
suppression sequences.
What accounts for the diagnostic “near
miss” in this case and how can mistakes like
this be avoided?
The physician in this case did not perform a careful
physical examination, perhaps because she fell prey to
the cognitive error of “premature closure.” No addi-
tional diagnoses were considered once a verdict that
“fits the facts” had been found. The physical exam-
ination findings in this patient were subtle, and his
sunglasses probably masked the eye abnormalities.
He refused funduscopic examination, but that is not
unusual in patients with primary headache disorders
who are sensitive to light. In addition, the patient’s
history was highly suggestive of a particular form of
benign headache, including the “classic” feature of a
94
foreign body sensation in the eye. The physician in this
case probably reasoned that she was unlikely to find
anything on physical examination and so skipped this
step.
When autonomic features occur in close associa-
tion with discrete episodes of headache pain, and espe-
cially if lacrimation or rhinorrhea also occur, the cause
is most likely to be benign activation of the autonomic
nervous system by a headache. It is easy to under-
stand how the physician in this case made a diagnosis
of hemicrania continua, especially since the feeling of
“grit” in the eye is a common complaint in that disor-
der. More careful examination, however, prompted by
the wife’s parting question about “squinting,” revealed
subtle neurologic signs that raised suspicion of a more
sinister explanation for the patient’s problem.
Physicians may perform brief physical exams for
many reasons: a shortage of time or a belief that the
diagnosis is clear based upon a characteristic history.
They may reason that therefore the physical examina-
tion is an afterthought, or wish to spare the patient dis-
comfort. In this case, several of these factors were likely
at play. This case is a reminder of the importance of a
thorough physical exam even if it means putting the
patient through temporary discomfort, such as expos-
ing a photophobic patient to a brief ophthalmologic
exam.
Discussion
Headache is present in roughly two-thirds of patients
with carotid dissection, and is usually ipsilateral to the
dissection. Horner’s syndrome is also common. A his-
tory of previous minor head or neck trauma, as in this
case, is also common. Dissection is thought to occur
when small tears in the intimal layer of the artery allow
arterial blood (which is under high pressure) to pen-
etrate into the medial layers of the arterial wall. The
resulting hematoma can produce partial or complete
occlusion of the artery, and emboli arising in this area
may also result in ischemia.
Cardiac risk factors such as hypertension or hyper-
cholesterolemia may raise the risk of dissection, as
do connective tissue disorders. Chiropractic manipu-
lation of the neck has also been associated with dis-
section of cranial arteries, and this is one reason we
do not recommend it for the treatment of headache.
Dissection is usually treated with either anticoagula-
tion or antiplatelet agents. A recent nonrandomized
study did not show clear benefit for either approach

so in view of the potential risks of full anticoagula-
tion, many physicians opt for treatment with aspirin
or other antiplatelet regimens.
Diagnosis
Carotid dissection with Horner’s syndrome.
Tip
A careful ophthalmologic examination is important
in all patients who present with headache. A cursory
examination can miss subtle but important findings.
An older woman with focal headache
Case
A 68-year-old woman was seen in the urgent care
department of the hospital because she had awakened
earlier that day with a headache. The pain was burn-
ing, throbbing, and located over the left temple and
forehead. She rated it 8 on a pain scale of 0–10. The
headache was not associated with additional symp-
toms such as nausea, vomiting, photo or phonophobia.
She had a remote history of episodic migraine without
aura but had not experienced any migraine headaches
for the last 12 years. Her physical examination was nor-
mal with the exception of elevated blood pressure of
178/96 mm Hg. Her neurologic examination was also
normal, with no bruits or tender or indurated tempo-
ral blood vessels.
What is the differential diagnosis?
There is a long list of diagnostic possibilities that
should be considered in an older patient with the sub-
acute onset of a new type of headache. This patient
has a history of migraine but her current headache has
few migrainous features. It would be unusual for severe
migraine to recur abruptly at this age.
Some sort of vascular problem is at the top of the
list of differential diagnoses in this case. While sud-
den, severe elevations in blood pressure can provoke
headache, this patient’s modest degree of hypertension
is an unlikely explanation for her headache. Could this
be a cerebral hemorrhage or infarct? This patient is
alert and has no focal neurologic deficits, making this
possibility less likely. Giant cell arteritis is a possibil-
ity, but this patient does not have additional systemic
signs or symptoms suggestive of that disorder. A mass
lesion of some sort or a slowly expanding subdural
Chapter 6: Missed historical features
hematoma is also a possibility, but again there are no
focal symptoms to support these diagnoses. An inflam-
matory process also seems unlikely.
What laboratory or other investigation
should this patient have?
A careful workup to exclude the dangerous diag-
noses discussed above is appropriate in this situation.
The patient in this case underwent a full battery of
blood tests, including an ESR and CRP. A computed
tomographic scan of the head with and without con-
trast showed no abnormalities, and a lumbar puncture
showed clear fluid with a normal pressure. The patient
was diagnosed with recurrent migraine. She was given
a prescription for acetaminophen with codeine and
advised to see her primary care physician in a few days
if the symptoms did not improve.
The pain continued over the next day and was only
partially relieved by acetaminophen with codeine. On
the afternoon of the second day, the patient began
to experience itching as well as pain and noticed the
development of a vesicular rash over her left forehead.
She saw her primary care physician who diagnosed
herpes zoster (shingles).
How should this patient’s herpes zoster
be treated?
Soothing topical lotions and analgesics are appropriate
symptomatic treatments for the rash of herpes zoster.
Eye involvement occurs in 10–25% of patients with
zoster, when zoster affects the ophthalmic division of
the trigeminal nerve. This patient should be referred
for ophthalmologic evaluation since zoster affecting
the eye can pose a threat to vision. Ophthalmologists
may prescribe antiviral eye drops, or ointments may be
helpful.
Because the pain of zoster can be intense, many
patients require the use of opioid analgesics. Most doc-
tors also treat patients with systemic antiviral agents
such as acyclovir or famciclovir. These may reduce the
duration of the attack and speed healing, but the drugs
are likely to be most effective when started as soon
as possible after symptoms begin, so time is of the
essence.
Timely use of antiviral agents may decrease the
chance that patients will develop persistent post-
herpetic pain, and additional treatment with cortico-
steroids may help some patient subgroups. Many
95
 Chapter 6: Missed historical features
doctors thus use both antiviral agents and steroids to
treat herpes zoster. Postherpetic neuralgia occurs in
10–18% of patients with zoster, and is frustrating to
treat. The usual treatment is amitriptyline, but results
are often disappointing and anticholinergic side effects
may limit its use in elderly patients. Carbamazepine
and gabapentin are also used.
Discussion
Herpes zoster results from spontaneous reactivation of
the varicella zoster (chickenpox) virus, which remains
latent in the sensory ganglia after the initial chicken-
pox infection. It is a common viral infection, with an
incidence of about 4 per 1000 people per year. The
elderly and immunocompromised individuals are at
highest risk. Zoster is easy to diagnose when the char-
acteristic vesicular rash is present but, as illustrated by
this case, pain may precede the appearance of the rash
by several days. In those patients, the severe localized
pain can easily be mistaken for other illnesses such as
migraine.
A zoster vaccine has recently become available and
is recommended for use in those over the age of 60.
It is intended to prevent zoster, and is not a treatment
for existing cases of shingles or postherpetic neural-
gia. One clinical trial suggested that vaccination of
1000 patients of age 60 or older would prevent one
case of postherpetic neuralgia over the subsequent
three years. Unfortunately, vaccination is least effec-
tive in patients who need it most: the very elderly and
those who are immunocompromised. Nonetheless, we
strongly recommend to all of our patients over the
age of 60 that they consider vaccination. There is no
evidence that pre-existing headache disorders such as
migraine increase the risk of developing zoster or its
complications, but we think it is worth minimizing the
chance that patients with an existing headache disor-
der will also have to cope with postherpetic neuralgia.
Diagnosis
Herpes zoster.
Tip
The diagnosis of herpes zoster is easily missed in
patients who present with pain and no rash. The pos-
sibility of herpes zoster infection should be considered
in elderly or immunocompromised patients with the
subacute onset of severe unilateral head pain.
96
A 27-year-old woman with weakness
and headache
Case
A 27-year-old woman presented to the headache clinic
for a new patient visit after moving to the area for work.
She had developed migraines at the age of six but was
otherwise healthy. Headaches had varied in frequency
over the years and were now occurring two or three
times a month. The headaches were typical of migraine
and a previous brain MRI had been normal.
The patient reported that all of her headaches were
preceded by right-sided numbness and weakness. She
could tell when a headache was likely because she
began to drop things and experienced some difficulty
walking. The patient had multiple family members
with migraine, but no one else had experienced pre-
ceding symptoms like hers. These symptoms typically
lasted about an hour and cleared as the headache
began.
Her previous neurologist had diagnosed hemi-
plegic migraine and told her that she should stop using
sumatriptan, which she had taken since she was 18
and which had worked well for her severe headaches.
Instead, he prescribed a butalbital-containing combi-
nation analgesic but the patient reported it was not
very effective.
Her new neurologist asked the patient to call for an
urgent appointment the next time she experienced an
episode of weakness. On examination during such an
episode, the patient had dense numbness of the right
hand, arm, foot, and calf. Her motor strength, however,
was 5/5 throughout. Because of this, her diagnosis was
revised to that of migraine with typical sensory aura
rather than hemiplegic migraine. She resumed the use
of sumatriptan, which was again effective.
What were the diagnostic possibilities based
on the history?
This patient had a long history of headaches that
met criteria for migraine and responded well to
migraine-specific therapy with triptans. She also expe-
rienced stereotyped focal neurologic deficits prior
to her headache episodes that from her description
sounded like transient right hemiparesis. The list of
diagnostic possibilities in this case includes migraine
with aura; familial or sporadic hemiplegic migraine; a
seizure disorder; vascular disorders such as arteritis or

transient ischemic attacks; mitochondrial myopathy,
encephalopathy, lactic acidosis, and stroke-like symp-
toms (MELAS); and cerebral autosomal dominant
arteriopathy with subcortical infarcts and leukoen-
cephalopathy (CADASIL).
Many of these diagnoses can be immediately
excluded based on the patient’s history. She had no
cognitive impairment or complex motor behavior
associated with her episodes, so a seizure disorder was
unlikely. MELAS or CADASIL were likewise improb-
able based on a normal brain MRI that showed no evi-
dence of prior infarcts or other abnormalities. Like-
wise, vascular disorders are an unlikely explanation for
headaches in a healthy young woman who has experi-
enced no permanent problems despite multiple similar
attacks over two decades.
About a third of patients with migraine expe-
rience focal neurologic deficits before a headache.
Typical aura symptoms can include visual, sensory,
or speech phenomena. Patients who experience true
motor weakness in association with migraine are clas-
sified separately as having hemiplegic migraine. This is
usually an inherited autosomal dominant disorder and
a number of single-gene mutations have been iden-
tified that are associated with hemiplegic migraine.
Non-familial cases also occur and are attributed to
spontaneous mutations. The patient’s history is sug-
gestive of transient hemiplegia in association with
headaches, so the differential diagnosis in this case is
between migraine with typical aura and hemiplegic
migraine.
What historical and physical examination
findings were at odds with the diagnosis of
hemiplegic migraine?
It can be challenging to discriminate between typical
migraine aura and hemiplegic migraine. These disor-
ders share many features of migraine including severe
headache and neurologic accompaniments to those
headaches. One common pitfall is accepting at face
value a patient’s report of motor weakness. Patients
can have difficulty distinguishing between sensory and
motor symptoms. Numbness can make it difficult to
grasp or hold objects, and the resulting clumsiness may
be interpreted as due to weakness. In this case, the
patient’s new physician correctly recognized that it was
important to examine the patient during an episode to
assess for objective signs of true motor weakness.
Chapter 6: Missed historical features
Other features of this patient’s presentation were
not wholly compatible with a diagnosis of hemiplegic
migraine. She did have a family history of migraine,
but no one else in the family had similar neurologic
accompaniments to headache. This makes a history
of hemiplegic migraine less likely since in most cases
there is a strong family history compatible with auto-
somal dominant transmission of the disorder. Speech
disturbances are also common in hemiplegic migraine,
but this patient had no speech component to her aura.
Additionally, this patient’s aura symptoms preceded
her headache and faded as the headache began. Most
patients with hemiplegic migraine experience aura
symptoms throughout the headache and occasionally
beyond.
How does the management of migraine
with typical aura differ from that of
hemiplegic migraine?
Vasoconstrictive medications such as triptans that
are routinely used for the treatment of patients with
migraine without aura and migraine with typical aura
are contraindicated in patients who have familial
hemiplegic migraine. This contraindication is based
on fears that triptans or ergots might be more likely
to cause vasoconstrictive complications in patients
who have complex forms of aura such as hemiplegic
migraine. There is no firm scientific foundation for
these worries, but formal package labeling contraindi-
cates the use of these agents. Because of this, most
physicians are understandably reluctant to allow their
use in patients who carry a diagnosis of hemiplegic
migraine.
Most patients with hemiplegic migraine have rel-
atively infrequent attacks. Depending upon the sub-
type, these are sometimes triggered by head injury,
emotional stress, or hormonal fluctuations. In most
cases of hemiplegic migraine the neurologic deficits
are reversible, but there are cases in which neuro-
logic deficits have progressed over time or become per-
manent. Because attacks are usually infrequent, most
patients do not require preventive medications. There
is a clinical impression, but no firm evidence, that
calcium channel antagonists or acetazolamide may
be more desirable preventive agents for hemiplegic
migraine than for migraine with typical aura. Many
physicians believe it is prudent to avoid beta-blockers
in patients with hemiplegic migraine.
97
 Chapter 6: Missed historical features
Discussion
Hemiplegic migraine is a diagnosis of exclusion that
can have serious implications for patients. In this case
the patient was prevented from using highly effec-
tive treatment for her migraine based on a mistaken
diagnosis of hemiplegic migraine. This could have
been avoided if the physician who made the diagno-
sis had made efforts to verify the patient’s report of
weakness.
Diagnosis
Migraine with typical (sensory) aura.
Tip
Patients can easily confuse numbness and weakness.
Patient reports of motor weakness in association with
headache should be verified by examination during an
episode.
Further reading
Typical aura with headache
Hansen JM, Lipton, RB, Dodick, DW, et al. Migraine
headache is present in the aura phase: a prospective
study. Neurology. 2012;79:2044–9.
Russell MB, Olesen J. A nosographic analysis of the
migraine aura in a general population. Brain.
1996;119:355–61.
Transformed migraine
Scher AI, Stewart WF, Buse D, Krantz DS, Lipton RB.
Major life changes before and after the onset of chronic
daily headache: a population-based study. Cephalalgia.
2008;28(8):868–76.
Scher AI, Stewart WF, Ricci JA, Lipton RB. Factors
associated with the onset and remission of chronic
daily headache in a population-based study. Pain.
2003;106(1–2):81–9.
Headache and maltreatment
Nelson HD, Bougatsos C, Blazina I. Screening women
for intimate partner violence: a systematic review
to update the U.S. Preventive Services Task Force
recommendation. Ann Intern Med. 2012;156(11):
796–808, W-279, W-280, W-281, W-282.
Norman RE, Byambaa M, De R, et al. The long-term health
consequences of child physical abuse, emotional abuse,
and neglect: a systematic review and meta-analysis. PLoS
Med. 2012;9(11):e1001349.
98
Tietjen GE, Brandes JL, Peterlin BL, et al. Childhood
maltreatment and migraine. Headache. 2010;50(1):
20–51.
Tietjen GE, Khubchandani J, Herial NA, Shah K. Adverse
childhood experiences are associated with migraine and
vascular biomarkers. Headache. 2012;52:920–9.
Teitjen GE, Peterlin BL. Childhood abuse and migraine:
epidemiology, sex differences, and potential
mechanisms. Headache. 2011;51:869–9.
HaNDL
Bartleson JD, Swanson JW, Whisnant JP. A migrainous
syndrome with cerebrospinal fluid pleocytosis.
Neurology. 1981;31:1257–62.
Berg MJ, Williams JS. The transient syndrome of headache
with neurologic deficits and CSF lymphocytosis.
Neurology. 1995;45:1648–54.
Krause T, Nolte CH. The syndrome of transient headache
and neurological deficits with cerebrospinal fluid
lymphocytosis (HaNDL) as an acute ischemic stroke
mimic leading to systemic thrombolysis: a case report.
Clin Neurol Neurosurg. 2012;114(6):689–90.
Nakashima K. Syndrome of transient headache and
neurological deficits with cerebrospinal fluid
lymphocytosis: HaNDL. Intern Med. 2005;44(7):690–1.
Low CSF pressure headache
Mokri B. Spontaneous low cerebrospinal pressure/volume
headaches. Curr Neurol Neurosci Rep. 2004;4(2):117–
24.
Tseng YL, Chang YY, Lan MY, Wu HS, Liu JS. Spontaneous
intracranial hypotension in a patient with reversible
pachymeningeal enhancement and brain descent. Chang
Gung Med J. 2003;26(4):293–8.
Carotid artery dissection
Kennedy F, Lanfranconi S, Hicks C, et al.; CADISS
Investigators. Antiplatelets vs anticoagulation for
dissection: CADISS nonrandomized arm and
meta-analysis. Neurology. 2012;79(7):686–9.
Parwar BL, Fawzi AA, Arnold AC, Schwartz SD. Horner’s
syndrome and dissection of the internal carotid artery
after chiropractic manipulation of the neck. Am J
Ophthalmol. 2001;131(4):523–4.
Patel RR, Adam R, Maldjian C, et al. Cervical carotid artery
dissection: current review of diagnosis and treatment.
Cardiol Rev. 2012;20(3):145–52.
Herpes zoster
Harpaz R, Ortega-Sanchez IR, Seward JF; Advisory
Committee on Immunization Practices (ACIP) Centers
for Disease Control and Prevention (CDC). Prevention

of herpes zoster: recommendations of the Advisory
Committee on Immunization Practices (ACIP). MMWR
Recomm Rep. 2008;57(RR-5):1–30.
Sanford M, Keating GM. Zoster vaccine (Zostavax): a
review of its use in preventing herpes zoster and
postherpetic neuralgia in older adults. Drugs Aging.
2010;27(2):159–76.
Chapter 6: Missed historical features
Hemiplegic migraine
Lafrenière RG, Rouleau GA. Identification of novel genes
involved in migraine. Headache. 2012;52:107–10.
Russell MB, Ducros A. Sporadic and familial hemiplegic
migraine: pathophysiological mechanisms, clinical
characteristics, diagnosis, and management. Lancet
Neurol. 2011;10(5):457–70.
99
 Chapter
Errors in management of acute headache
7
Nearly every patient who experiences headache will
use some form of therapy to treat his or her acute
headaches. Also known as abortive or symptomatic
therapies, these treatments are intended to relieve the
pain of headache, as well as accompanying symptoms
such as nausea. Acute therapies can range from non-
pharmacologic treatments such as topical ice or heat,
to nonspecific over-the-counter and prescription anal-
gesics, to treatments specific to the headache type.
Triptan therapy for treatment of migraine falls into this
last category.
In addition to the particular pitfalls illustrated
by the cases in this chapter, a few general princi-
ples should be kept in mind. Treatments for acute
episodes of headache are generally more effective when
taken early in the headache, before central sensitiza-
tion develops. One study showed that triptans were
less effective once cutaneous allodynia (a marker for
central sensitization) had developed. Unfortunately,
many patients wait until a full-blown headache has
developed before taking a triptan, so education about
the importance of treating early can by itself improve
response rates.
When a single treatment for headache is not
effective, a combination of treatments may be more
effective. For example, some patients respond well
to a combination of triptans and nonsteroidal anti-
inflammatory drugs (NSAIDs) but not to either med-
ication given alone. Likewise, patients who develop
nausea early in the course of their migraines will
likely have a better response to oral triptan ther-
apy if they are also treated with an antiemetic. The
phenothiazine antiemetics (such as promethazine and
prochlorperazine) probably have some intrinsic anti-
migraine effects as a result of their anti-dopaminergic
effects.
Lastly, it is worth mentioning the debate about
whether stepped or stratified care is a better approach
to treatment of acute headaches. In stepped care,
100
patients treat headaches first with a nonspecific agent
such as an NSAID, and then go on to a specific ther-
apy (usually a triptan) only if the NSAID is not effec-
tive. In stratified care, patients use nonspecific agents
as first-line therapy for less severe and specific thera-
pies as first line for more severe headaches; in other
words, the treatment is tailored to the patient’s indi-
vidual circumstances. A randomized trial comparing
stepped care with stratified care in the treatment of
acute migraine showed that stratified care was more
effective and associated with higher patient satisfac-
tion. For this reason, we strongly recommend that
patients with troublesome migraine should be treated
with stratified care approaches rather than required to
fail therapies that are usually ineffective before being
allowed to use highly effective therapy.
A migraineur who does not respond to
triptan treatment
Case
A 30-year-old woman was referred for consultation
because of recurrent headaches for several years. She
was in good health and her neurologic examination
was normal. Her headaches met diagnostic criteria for
migraine without aura and occurred on average twice
a month. She had successfully treated headaches with
550 mg of naproxen sodium until two years ago when
she underwent gastric bypass surgery for obesity. Post-
operatively, the surgeon told her that she should not
use naproxen or other nonsteroidal anti-inflammatory
drugs. To replace naproxen she was given a prescrip-
tion for 1 mg naratriptan tablets. These were not effec-
tive, so her physician prescribed 2.5 mg of zolmitrip-
tan, which also did not help.
Eventually the patient was given a prescription for
oxycodone. This partially relieved her headache pain
but produced nausea and made it impossible for her to

function at her job as a nurse. The patient tried several
migraine preventive drugs that were not tolerable or
effective. She does not want to take medicine every day
for something that happens only twice a month.
Why should NSAIDs be avoided after
bariatric surgery?
Gastric ulceration is a well-known side effect of
NSAIDs. Bariatric surgery does not necessarily
increase the risk of gastric ulceration. Rather, ulcer-
ations that do occur can be more difficult to detect
after bariatric surgery and may produce more serious
complications. Thus most bariatric surgeons recom-
mend that patients avoid this class of drugs following
surgery.
The most common type of gastric bypass surgery
in the United States is the Roux-en-Y gastric bypass,
which sections off a portion of the stomach into a
small pouch to limit food intake. The small intestine
is repositioned and connected to the pouch at the top
of the stomach, where its narrow opening slows stom-
ach emptying. After this procedure the stomach cannot
easily be visualized with gastroscopy, making it diffi-
cult to detect ulcers if they are suspected. Nonsteroidal
anti-inflammatory drugs also may increase the risk of
anastomotic leakage. Finally, because the active por-
tion of the stomach is very small, any ulceration that
does occur covers a larger proportion of the total sur-
face of the stomach.
A common misconception among patients and
some physicians is that avoiding oral ingestion of non-
steroidal anti-inflammatory medications will circum-
vent this problem. Nonsteroidal anti-inflammatory
drugs can be administered intranasally, parenterally,
or as rectal suppositories, but these formulations do
not reduce the risk of stomach ulceration. The risk of
gastric ulceration is related to systemic inhibition of
prostaglandins and not to direct irritation of the gastric
mucosa, so non-oral administration of NSAIDs does
not reduce the risk.
What are the possible explanations for this
patient’s failure to respond to triptans?
Triptans are very effective but do not work for every-
one. One possibility is that this patient is truly refrac-
tory to triptans. On the other hand, it is possible that
she has been treated with subtherapeutic doses or for-
Chapter 7: Errors in management of acute headache
mulations of triptans or that treatment has not been
properly timed. In our experience, these are the most
common explanations for an apparent lack of response
to triptan treatment.
Clinical trials suggest that the maximum response
rate to triptans is approximately 70%, although in
clinical practice they seem to be slightly less effec-
tive, with response in about 60% of treated attacks.
The likelihood of a good response to a triptan seems
to depend on the dose and formulation of the drug,
and the timing of treatment. A recent meta-analysis
of sumatriptan trials showed the 100 mg dose was
effective for a larger percentage of patients than the
50 mg dose, which in turn was more effective than
the 25 mg dose. This dose–response relationship has
been demonstrated for other triptans. The patient in
this vignette was treated with the lowest commercially
available doses of naratriptan and zolmitriptan. It is
possible that higher doses of these drugs (e.g. 2.5 mg of
naratriptan or 5 mg of zolmitriptan) would have been
effective.
Most patients prefer oral migraine treatments but
parenteral drugs have higher bioavailability. The ther-
apeutic gain for subcutaneous sumatriptan, for exam-
ple, is higher than for any of the oral triptans.
Intranasal formulations of sumatriptan and zolmitrip-
tan are available, but these are not more effective than
oral triptans. Only a small amount of these intranasal
triptans is absorbed through the nasal mucosa; rather,
most of the liquid drips down the back of the throat,
is swallowed, and absorbed through the gastrointesti-
nal tract in the same way as orally administered drugs.
Likewise, the orally disintegrating formulations of
rizatriptan and zolmitriptan are not well absorbed sub-
lingually but dissolve and are swallowed. The patient in
this case was treated with oral triptans, and it is possi-
ble that parenteral sumatriptan would have been more
effective.
Finally, the timing of drug administration may
spell the difference between successful triptan treat-
ment of a migraine attack and apparent drug fail-
ure. Some research suggests that triptan treatment is
less likely to be effective when delayed until headache
intensity is severe or the attack is well established. This
lack of benefit may be due to the development of cen-
tral sensitization. We do not know at what point in
her headaches this patient treated her attacks, but it is
possible that early treatment when the headaches were
mild would have been more effective.
101
 Chapter 7: Errors in management of acute headache
Table 7.1. Selected strategies for optimizing triptan treatment
of acute headache
Use adequate doses
Try a different triptan
Try combination therapy
– Triptans with NSAIDs
– Triptans with antiemetics
Treat early
Use alternative formulations (nasal spray, injection, orally
dissolving tablet)
Discussion
Most patients with migraine or cluster headache
respond to a triptan if the right dose and formulation
are used. Treatment is most effective when adequate
doses of the drug are used early in a headache. Thus,
our position is that “no patient has failed a triptan
until they have failed a full dose of an injectable trip-
tan given early in a headache.” In practice, this means a
6 mg dose of subcutaneous sumatriptan administered
as soon as the headache begins. In our experience, the
subcutaneous formulation of sumatriptan is remark-
ably underused and is often effective in patients who
have apparently “failed” triptan therapy. It is admin-
istered using an auto-injector that can hold cartridges
of 6 or 4 mg of sumatriptan. The dose can be repeated
at any point after two hours if needed. The maximum
daily dose is 12 mg, which translates to two 6 mg or
three 4 mg injections in a 24-hour period.
If triptans alone are not effective, or are only par-
tially effective, we commonly recommend that patients
use them in combination with an NSAID. (Obviously,
however, that is not an option for the patient in the
vignette.) Naproxen sodium is available in a fixed-dose
tablet formulation with sumatriptan, but this combi-
nation pill is expensive. Unless patients prefer the con-
venience of a single tablet, we prefer to provide this
combination of treatments using separate pills. This
also allows for customization of the dose of both trip-
tan and the NSAID. For patients who have prominent
nausea, we may even add a third anti-nausea drug to
this regimen, such as 10 mg of metoclopramide or a
promethazine rectal suppository, a regimen we refer to
as “triple therapy.” Strategies for improving treatment
results of acute headache using triptans are summa-
rized in Table 7.1. Many of these are generalizable to
other forms of treatment for acute migraine as well.
Diagnosis
Migraine without aura.
102
Tip
It is a mistake to conclude that patients do not respond
to triptans without ensuring that they have used an
adequate dose and formulation early in a headache.
A young woman with chest pressure
from sumatriptan
Case
A 19-year-old woman with episodic migraine with-
out aura was seen in the emergency department (ED)
with a headache and nausea. The headache was sim-
ilar to her previous attacks but had not responded to
her usual treatment of 1000 mg of aspirin and 10 mg
of metoclopramide. Her neurologic examination was
normal. She had no other major medical problems
or illnesses and was taking no regular medications.
She was given a subcutaneous injection of 6 mg of
sumatriptan. Her headache disappeared and nausea
improved, but she experienced chest pressure and neck
tightness lasting 15 minutes. She had no associated
symptoms. She had an electrocardiogram that was nor-
mal and was referred for outpatient cardiovascular
evaluation.
Were the electrocardiogram and
cardiovascular investigation indicated?
No. This young patient at low risk of cardiovascular
disease experienced short-lived chest pressure in close
temporal relation to an injection of sumatriptan. Non-
serious side effects such as flushing, paresthesias, and
transient neck or chest tightness are well-recognized
triptan side effects. They occur often enough that they
are referred to as “triptan sensations.” They usually
begin within a few minutes to half an hour of drug
administration and can last up to an hour, although
in our experience they are typically of relatively short
duration. For unclear reasons, triptan sensations seem
to be most common in younger women such as the
patient in the vignette.
Triptan sensations may frighten patients and doc-
tors because of their similarity to more serious car-
diac symptoms. Although cardiovascular events, some
serious, have been reported with triptan use, they are
not common. Most have occurred in patients with
many risk factors for coronary artery disease. Research
suggests that the clinically used doses of triptans do
 Chapter 7: Errors in management of acute headache

Table 7.2. Triptan characteristics.

Generic Brand
name name Formulations Dosing Comments
Almotriptan Axert Tablet 12.5 mg
Eletriptan Relpax Tablet 20/40 mg
Frovatriptan Frova Tablet 2.5 mg Longest half-life
Naratriptan Amerge Tablet 1/2.5 mg Second longest half-life
Rizatriptan Maxalt Tablet 5/10 mg Decrease dose when used with
Orally disintegrating tablet 5/10 mg propranolol
Sumatriptan Imitrex Tablet 25/50/100 mg Also available in a fixed-dose
Nasal spray 5/20 mg combination tablet containing
Subcutaneous injection 4/6 mg sumatriptan and naproxen
Zolmitriptan Zomig Tablet 2.5/5 mg
Nasal spray 5 mg
Orally disintegrating tablet 2.5/5 mg

not cause coronary artery constriction sufficient to
provoke myocardial ischemia. Furthermore, studies
of patients who have chest or neck pain with triptan
administration have not shown electrocardiographic
or other evidence of reductions in myocardial perfu-
sion. Based on this evidence, we do not believe that car-
diovascular evaluation is warranted in young patients
like the one in this vignette who have transient triptan
sensations.
Should this patient be advised to
avoid triptans?
There is no safety reason for this patient to avoid the
use of triptans in the future. Sumatriptan was effec-
tive for a severe headache that had not responded
to nonsteroidal anti-inflammatory treatment. She is
likely to have similar bad headaches in the future. It is
important not to foreclose the use of an effective treat-
ment unnecessarily. We find that many of our patients
believe the benefits of sumatriptan outweigh short-
lived side effects such as chest pain, especially once
they are reassured these side effects are not serious.
Furthermore, most patients who are prone to triptan
sensations do not experience them every time they
take a triptan, and those who do often come to view
them as a sign that “the drug is working.”
Triptan sensations may be more common in
patients who receive parenteral rather than oral trip-
tans, so one strategy for this patient might be to use an
oral formulation of sumatriptan. In one study about
half of patients treated with subcutaneous sumatrip-
tan reported such side effects compared with roughly
a quarter who were treated with the oral drug. If the
problem recurred with the use of oral sumatriptan, and
was troubling to the patient, it would still be worth-
while to try a different oral triptan. Although triptan
sensations can occur with any triptan, for individual
patients the adverse effect profile of the different trip-
tans may vary.
Since there are relatively few classes of drugs that
can be used to treat individual migraine attacks, it is
important to maximize the chances of success when
a triptan is first prescribed. We find it useful to warn
patients about the possibility of transient triptan sen-
sations before they try the drug for the first time. This
reduces the likelihood that they will be frightened if
such symptoms occur and then refuse to use the drug
again – thus foreclosing use of a highly effective treat-
ment option. For patients who are very anxious about
the possibility of triptan side effects, we sometimes
suggest that they try the drug for the first time when
they do not have a headache. This allows them to expe-
rience the effects of the drug without the added anxiety
produced by a bad headache, and makes it possible to
separate the side effects of the drug, if any, from the
symptoms of a headache.
Discussion
Triptans have been in widespread clinical use since
their introduction in the early 1990s, and have a good
record of safety and tolerability. Table 7.2 lists the char-
acteristics of the seven triptans that are available in the
United States. All are US Food and Drug Administra-
tion (FDA) approved for treatment of acute migraine
and sumatriptan injections are FDA approved for
treatment of acute cluster headache. Triptans are

103
 Chapter 7: Errors in management of acute headache
appropriate treatment for patients whose attacks do
not reliably respond to simple analgesics, which was
the case for this patient. They provide good relief of
pain and headache-related symptoms such as nausea.
For most patients, triptans have a more favorable
side effect profile than other choices for treatment
of acute migraine. Unlike opioids and barbiturate-
containing medications, triptans do not generally pro-
duce sedation or cognitive impairment, nor are they
associated with the development of abuse and depen-
dence syndromes. Unlike NSAIDs, triptans do not
impose a risk of gastrointestinal bleeding. Overuse of
triptans may produce medication overuse headache,
but evidence suggests that it is simpler to treat medica-
tion overuse headache that results from triptans than
that resulting from overuse of opioids or barbiturates.
These are important long-term considerations.
Unlike minor, transient side effects such as triptan sen-
sations, these more serious adverse events must be
taken into account when deciding what treatment to
use for individual migraine attacks. Although treat-
ment for individual headaches is used intermittently,
migraine is a chronic condition for which such treat-
ment will be used repeatedly over many years. Thus,
adverse effects that are inconsequential when treat-
ment is used for a single attack can be very important
with long-term regular use. Conversely, side effects
such as triptan sensations which are more unpleas-
ant within the context of an individual headache may
nonetheless not be as important in the larger perspec-
tive of treatment decisions.
Diagnosis
Migraine without aura and transient “triptan sensa-
tions” with sumatriptan.
Tip
Transient triptan sensations such as chest pressure,
paresthesias, or flushing are common, nonserious side
effects of triptans. When they occur in patients at low
risk for cardiovascular disease they do not warrant car-
diac investigation or require avoidance of triptans.
Worries about serotonin syndrome
Case
A 45-year-old female presented for evaluation of
headache that had begun when she was in her late
104
teens. Attacks were frequently related to her menstrual
cycle. During each of two pregnancies, she had been
free of headache. Since her second delivery, however,
she had noted headaches with every menstrual period
that were moderate to severe in intensity, lasted for two
days each, and limited her activities. Each headache
began with a prodrome of cervical muscle spasm after
which she developed unilateral throbbing frontal and
retro-orbital pain, increasing with physical activity and
associated with photo and phonophobia and rare nau-
sea. NSAIDs and oral sumatriptan were of incomplete
benefit. She had previously been advised to try suma-
triptan by injection but was reluctant since she recalled
being told that it was contraindicated because she was
also taking a low dose of sertraline. Her primary care
physician had prescribed the sertraline for situational
depression after a recent divorce.
The headache specialist told the patient that in his
opinion the risk of using a triptan in combination with
a selective serotonin reuptake inhibitor (SSRI) was low.
He recommended early use of the sumatriptan injec-
tion in the hopes of reducing her typical level of dis-
abling symptoms. The pharmacist, however, refused to
fill the prescription without contacting the physician,
citing the potential for a severe interaction between the
sumatriptan and the sertraline. The patient was told
that this was a “class one interaction.” The patient, con-
vinced that her prior worries had been warranted and
now suspicious of the medical advice she had received,
left the pharmacy without the prescription and can-
celled her return visit to the headache clinic.
Were the physician’s treatment
recommendations appropriate?
A 2006 FDA warning advised caution in the use of trip-
tans with other serotonergic drugs because of worries
about serotonin syndrome. Experts have called the evi-
dence used as the basis for this warning into question.
For one thing, the concomitant use of SSRIs and trip-
tans is very common, yet an epidemic of serotonin syn-
drome has not emerged. One study suggested that as
many as 65 million patients in a one-year period in
the United States were using an SSRI along with a trip-
tan with no documented cases of serotonin syndrome
identified among them. An American Headache Soci-
ety Position Paper published in 2010 stated that “The
currently available evidence does not support limiting
the use of triptans with SSRIs or selective serotonin–
norepinephrine reuptake inhibitors (SNRIs), or the use

of triptan monotherapy, due to concerns for serotonin
syndrome (Level U). However, given the seriousness
of serotonin syndrome, caution is certainly warranted
and clinicians should be vigilant to serotonin toxicity
symptoms and signs to insure prompt treatment.”
Many physicians and patients believe that men-
strual migraine is often more severe and resistant to
treatment than migraines occurring at other times
of the month. Early and aggressive management can
therefore be appropriate and necessary. In patients
who do not respond to oral therapy, such as this
one, treatment can include recommendations for an
injectable triptan. As in this case, the goal is to reduce
disability and improve the ability to function during
this monthly event.
Is there anything that the provider could
have done differently to avoid the patient
leaving care?
Possibly. The provider could have warned the patient to
expect advice of an interaction from the pharmacy and
discussed the basis of his advice with her. The phar-
macist, if concerned, could have discussed the mat-
ter with the physician to understand more fully the
reasons for use of the agents before approaching the
patient; a more balanced discussion may have resulted.
Discussion
Many headache specialists, feeling confident about the
low risk of serotonin syndrome with concomitant use
of SSRIs/SNRIs and triptans, and with limited time
to spend with patients, may omit discussion of this
matter. However, patients who search for information
about these drugs online will encounter multiple sites
which describe a “major interaction” that is “rare but
serious and potentially fatal” and typically warn that
concomitant use should be avoided.
Decision support software embedded in many elec-
tronic medical records will often show a warning when
such agents are prescribed together, and presumably
pharmacy software also produces similar warnings.
Accumulated evidence is quite compelling, however,
that the risk of serotonin syndrome with concomi-
tant use of triptans and selective serotonin reuptake
inhibitors is very low. Even after years of experience
with triptans, however, pharmacists continue to con-
tact our office frequently to discuss the possibility
of serotonin syndrome. Unfortunately, as in the case
Chapter 7: Errors in management of acute headache
Table 7.3. Selected symptoms of serotonin syndrome
Tachycardia
Hypertension
Hyperthermia
Clonus (inducible or spontaneous)
Ocular clonus (slow horizontal eye movements)
Tremor
Hyperreflexia
Agitation or restlessness
Hypertonicity (muscle rigidity)
Autonomic signs: diaphoresis, dilated pupils, flushing, increased
bowel activity
above, these “stops” can lead to disruption of care for
the patient and contribute to distrust of the medical
establishment.
The serotonin syndrome results from enhanced
serotonergic activity in the brain usually as the result
of use of medications which can increase serotoner-
gic activity, either alone or in combination. This results
in a constellation of symptoms and signs listed in
Table 7.3 that include restlessness, confusion, auto-
nomic instability, muscular irritability, tremor or
myoclonus, and even coma.
Diagnosis
Menstrually related migraine.
Tip
Good quality evidence suggests that the risk of sero-
tonin syndrome is low when triptans are prescribed in
combination with other serotonergic drugs. It is pru-
dent to discuss the balance of benefits and harms with
patients prior to prescribing this combination of treat-
ments, however, in order to avoid misunderstandings
later.
A patient with sulfa allergy and
migraine
Case
A young woman with episodic, infrequent migraine
with aura not controlled with over-the-counter med-
ications presented asking for better treatment of her
individual attacks of headache. She was given a pre-
scription for sumatriptan to manage her occasional
105
 Chapter 7: Errors in management of acute headache
Figure 7.1 A sulfonamide group.
O O
S R3
R1 N More technically, the sulphonamide-containing
R2
attacks, and appropriate use and side effects of the
drug were discussed. The next day, the pharmacy called
the office to notify the provider that the patient had
a documented allergy to sulfa. Because the suma-
triptan molecule contains a sulfa group (depicted in
Figure 7.1), the pharmacist wanted to know if the
patient should be switched to a different triptan.
Should the patient be switched to
a different medication?
Of the seven commercially available triptans, nara-
triptan, eletriptan, and almotriptan all contain sulfon-
amide groups. These sulfa moieties are folded within
the molecule and are not exposed, however. They do
not appear to produce cross-reactivity in patients who
are allergic to sulfonamide antibacterial drugs. The
package insert for sumatriptan notes that hypersen-
sitivity reactions to sumatriptan are rare but may be
more likely in patients with hypersensitivity to mul-
tiple medications. In our experience, most patients
with a history of sulfa allergy can use sulfonamide-
containing non-antibacterial medications without risk
and it would be reasonable to advise the patient in this
case to fill her prescription. If her previous sulfa reac-
tion was anaphylactic in nature, however, we would err
on the side of caution and consider prescription of a
triptan such as rizatriptan which does not contain a
sulfa moiety. Otherwise, the patient could be advised
not to be alone the first time she takes the medication.
Discussion
A number of studies have examined the question
of cross-reactivity in patients who are allergic to
sulfonamide-containing antibiotics, to which allergy is
relatively common (3%), and other medications that
contain sulfa moieties. The mechanism of the allergy
to the antibacterial drugs is not completely under-
stood and all types of hypersensitivity reaction have
been described. Many studies, however, have failed
to show clear cross-reactivity with other sulfonamide-
containing medications and suggest that structural dif-
ferences between the sulfonamide-containing antibi-
106
otics and non-antibiotics may explain the lack of
association.
antibiotics are sulfonylarylamines, in which the sul-
fonamide moiety is attached to a benzene ring, and
have an amine at the N4 position. The triptans are
simple sulfonamides, in which the sulfonamide moi-
ety is not connected to a ring structure. Incidentally
the intermediate group, which includes carbonic anhy-
drase inhibitors, has the sulfonamide moiety attached
to the ring structure but without the N4 amine.
It does appear that patients allergic to sulfon-
amide antibiotics may in general have a greater risk
of allergy to other medications, thus creating a general
increased risk of hypersensitivity but not a specific risk
in relation to the sulfonamide derivatives. Given the
described structural differences, and the lack of clini-
cal reports of cross-reactivity between sulfa antibiotics
and triptans, the risk of sumatriptan use in a patient
with sulfa allergy is likely to be low.
In this case, the patient was reassured and went on
to use sumatriptan without incident.
Diagnosis
Episodic migraine; sulfa allergy.
Tip
Although sumatriptan contains a sulfa moiety, it is
not attached to a benzene ring. Cross-sensitivity in
patients allergic to sulfonamide antibiotics is thus not
likely to occur.
Adverse effects associated with regular
long-term NSAID use
Case
A 45-year-old woman presented with headaches that
had begun when she was in graduate school and which
had gradually increased in frequency. They were now
present more days than not. They were bifrontal, vise-
like in quality, moderate in severity, and associated
with low-grade phonophobia but not photophobia or
nausea. The headaches were not worse with exercise
and there was no aura. These headaches generally
responded well to ibuprofen 400–800 mg, depending
on severity, and she had been taking ibuprofen at least
four days per week for as long as she could remem-
ber, sometimes requiring multiple doses a day. She had

previously been diagnosed with tension-type headache
and advised to continue ibuprofen, which she was told
was the best treatment for tension-type headache. A
friend of hers recently experienced liver damage as
a result of excessive use of acetaminophen. This had
caused her to wonder about whether it was safe to con-
tinue taking ibuprofen.
How would you advise this patient, and is
any further evaluation indicated?
This patient has been taking NSAIDs for many years,
and is therefore at risk for some of the health con-
sequences of chronic NSAID use. Gastritis is the
most common adverse effect associated with NSAIDs,
and all patients taking NSAIDs should be queried
about symptoms of heartburn or other signs of gastro-
esophogeal reflux disease. Patients who are on chronic
NSAIDs should probably also have renal function
checked periodically. Lastly, NSAID use may increase
the risk of cardiovascular events in patients with heart
disease, and risk factors for heart disease should be
evaluated periodically.
Upon further questioning, this patient reported
progressively worsening heartburn over the last sev-
eral years. She did not connect it with ibuprofen use
as she had been using ibuprofen for many years and
the heartburn had only developed recently. She had
not been to a doctor in many years because she was
healthy aside from her headaches, and she had not had
lab work in the last five years. A creatinine level was
obtained at her presenting visit and was 1.4 mg/dL.
What treatment options are available for
this patient’s headaches, and what could
have been done to prevent her kidney
problems?
This patient has experienced two possible compli-
cations of chronic NSAID use, namely gastritis and
mild chronic renal failure. Because of these adverse
events, she should be advised to discontinue the use of
NSAIDs. In addition to these adverse events, the pos-
sibility that her chronic headaches are due to medica-
tion overuse should also be considered. If that is the
case, her headaches may ultimately improve once she
has discontinued the daily use of analgesic medications
(although they may worsen temporarily as a result of
drug withdrawal). If headaches do not improve fol-
Chapter 7: Errors in management of acute headache
lowing NSAID withdrawal, the patient would bene-
fit from preventive therapy to reduce the frequency
of headaches and the need for treatment of individual
headaches.
Ideally, this patient’s chronic headaches would have
been recognized as a problem many years ago, and
she might have been offered preventive therapy for
them, perhaps when she initially presented to her
physician’s office and had been diagnosed with chronic
tension-type headaches. Although NSAIDs are first-
line therapy for treatment of many acute headache
disorders, they are less appropriate in patients who
have chronic headaches. Their use should be care-
fully monitored in patients with frequent headaches
because daily or near-daily use can lead to medication
overuse headaches and other complications. If patients
are maintained on long-term NSAID treatment, regu-
lar monitoring for development of gastric or renal side
effects is usually in order.
Discussion
NSAIDs are commonly used to treat many types
of headache. Ibuprofen and naproxen are often
used for tension-type headache or migraine, while
indomethacin is a first-line therapy for the rela-
tively uncommon syndromes of hemicrania continua,
paroxysmal hemicranias, and exertional headaches.
NSAIDs are also one of the most common over-the-
counter treatments for headaches, particularly among
patients with milder headache or those who have
not sought medical treatment. Despite their nonpre-
scription status, NSAIDs are associated with sub-
stantial risks, particularly when used long term or
frequently. Important risks include gastrointestinal
events, including gastritis, peptic ulcer disease, and
gastrointestinal bleeding, and an increased risk of car-
diovascular events. These two risks are listed in a black
box warning on the prescription form of ibuprofen,
and both of these risks may increase with prolonged
duration of use. Indomethacin seems particularly
prone to produce gastroduodenal toxicity.
Another potential adverse effect from long-term
NSAID use is renal papillary necrosis, which can lead
to renal failure. It is suspected that this is related to
prostaglandin inhibition by NSAIDs; prostaglandins
are responsible for pre-renal vasodilation and thus
help maintain renal blood flow. Patients with pre-
existing renal insufficiency, the elderly, and those tak-
ing diuretics or angiotensin-converting enzyme (ACE)
107
 Chapter 7: Errors in management of acute headache
inhibitors seem to be at the highest risk of renal com-
plications with NSAIDs. Many patients return to base-
line renal function after discontinuation of NSAIDs,
but this may be more likely if the renal dysfunction
is discovered early. In this case, it appeared that the
patient’s renal function had been compromised for
some time, because her creatinine remained elevated
despite discontinuation of NSAIDs.
Diagnosis
NSAID-induced gastritis and mild chronic renal fail-
ure; chronic tension-type headache.
Tip
Chronic use of NSAIDs can be associated with gas-
tritis, renal failure, and cardiovascular events. Risks
increase with duration of use and appropriate moni-
toring for safety is necessary.
Agitation after intravenous treatment
for acute headache
Case
A 37-year-old woman with migraine was brought to
the ED by her boyfriend. She had been suffering from
a typical migraine headache that had begun the pre-
vious morning. It had not responded to several doses
of her usual treatment of 6 mg subcutaneous suma-
triptan and oral metoclopramide. For prevention of
migraines, she also took venlafaxine 75 mg daily, topi-
ramate 50 mg twice daily and lisinopril 10 mg daily. She
had no neurologic findings on examination and fur-
ther testing was not felt necessary. An intravenous line
was placed and she was hydrated with normal saline
and given 30 mg of intravenous ketorolac and 10 mg
of intravenous prochlorperazine.
About an hour after receiving this treatment, the
patient became restless and agitated. When asked how
she was feeling she reported that she felt “terrible . . . I
just can’t explain it. I feel so bad and I can’t lie still.”
Assuming that the patient was restless because of pain,
an additional dose of 5 mg of intravenous prochlor-
perazine was administered. Ten minutes later the
patient experienced a prolonged tightening of her right
sternocleidomastoid muscle. Her chin was drawn
down towards the right shoulder and she developed
slurred speech. This slowly resolved but was followed
108
within 15 minutes by a similar episode involving the
right side.
Given the clinical description provided,
what is the likely cause of this patient’s
symptoms? Was the additional
prochlorperazine a good idea?
This patient’s agitation and uncontrolled muscular
movements were typical of extra-pyramidal side effects
that can occur with neuroleptic medications. Two
types of extra-pyramidal side effects are relevant to
migraine treatment: neuroleptic-induced acute dys-
tonia results in abnormal muscle contractions with
spasm or twisting of the head and abnormal move-
ments of the trunk or limbs. Episodes of dystonia
usually last 20–30 minutes and often produce pain.
One well-described form of dystonia is the oculo-
gyric crisis, in which the eyes deviate together to one
side. Neuroleptic-induced akathisia is characterized
by severe motor restlessness and agitation. This can
be more difficult to recognize than dystonia. Patients
may pace the room or rock from side to side if in
bed. Dystonia and akathisia may occur separately or
together; typically dystonic symptoms precede those of
akathisia, although that was not so in this case.
The correct diagnosis of extra-pyramidal side
effects in patients receiving neuroleptics for the treat-
ment of migraine is a challenge. The differential diag-
nosis also includes neuroleptic malignant syndrome,
serotonin syndrome, tricyclic antidepressant overdose,
or cocaine intoxication, so a careful review of all pos-
sibilities is in order. An important management pit-
fall is that the agitation and discomfort associated
with extra-pyramidal symptoms are easily mistaken
for anxiety or for residual pain, as occurred in the case
presented. Patients may then be given additional neu-
roleptic medication in the mistaken belief that pain
is the problem. In hindsight, the additional 5 mg of
prochlorperazine was a mistake.
How should this patient’s symptoms be
treated? Can neuroleptic-induced
extra-pyramidal symptoms be prevented?
The traditional approach to treating neuroleptic-
induced extra-pyramidal symptoms involves discon-
tinuation of the offending neuroleptic drug. In addi-
tion, anticholinergic agents such as diphenhydramine

or benztropine, or benzodiazepines, are often admin-
istered in the belief that they will cause more rapid
resolution of symptoms. Anticholinergic agents are
believed to work because extra-pyramidal reactions
involve an imbalance between central dopaminer-
gic and cholinergic systems. The acute blockade of
dopaminergic systems by the neuroleptic drug is the-
orized to result in an excess of cholinergic activity.
The dose of diphenhydramine is typically in the range
of 0.5–1.0 mg/kg and for benztropine it is 0.010–
0.015 mg/kg, both administered intramuscularly.
Good quality evidence suggests that anticholiner-
gic medications are effective in treating neuroleptic-
induced dystonia. Evidence is conflicting, however,
about whether diphenhydramine or benzodiazepines
should be used to treat akathisia. In our view, both
drugs probably work but the evidence is stronger and
more consistent for benzodiazepines. A study com-
paring diphenhydramine and midazolam for the treat-
ment of acute akathisia due to metoclopramide found
that midazolam was more effective than diphenhy-
dramine, although sedation was a prominent side
effect. A recent Cochrane Collaboration review also
supports the view that benzodiazepines are effective
for treatment of acute akathisia.
Given the discomfort associated with neuroleptic-
induced extra-pyramidal side effects, it is reasonable
to wonder whether these symptoms can be prevented.
A randomized double-blind controlled trial compared
midazolam 1.5 mg IV, diphenhydramine 20 mg IV,
or placebo on the occurrence of akathisia related to
metoclopramide used for the ED treatment of nau-
sea or headache. Midazolam was effective in prevent-
ing akathisia but diphenhydramine was no more effec-
tive than placebo. Thus, benzodiazepines appear to
be superior to diphenhydramine for both acute treat-
ment and prevention of neuroleptic-induced extra-
pyramidal symptoms. Another study suggested that a
slower infusion rate of metoclopramide (15 minutes
versus 2 minutes) lowered the incidence of akathisia
without reducing the effectiveness of the drug for
nausea.
Discussion
Neuroleptic medications such as prochlorperazine,
metoclopramide, and chlorpromazine successfully
relieve pain and nausea associated with acute attacks
of migraine. They are the drugs of choice for severe
headaches that have not responded to specific anti-
Chapter 7: Errors in management of acute headache
migraine therapy or where such therapy is contraindi-
cated. Intravenous treatment with prochlorperazine
10 mg or metoclopramide 20 mg, given with diphen-
hydramine 25 mg, is more effective than placebo for
acute migraine, and three-quarters of patients receiv-
ing these treatments say they would want them for
their next headache. In fact, one study suggested
that the combination of prochlorperazine and diphen-
hydramine was more effective than sumatriptan for
migraine in the emergency setting.
Neuroleptic-induced extra-pyramidal symptoms
are, however, important potential side effects that must
be kept in mind when using these drugs. These effects
are more common with prolonged administration but
can also complicate short-term therapy. In fact, they
can appear within minutes of treatment initiation.
Their reported prevalence varies, but a reasonable esti-
mate is that they may occur in about 20% of individ-
uals who receive intravenous neuroleptic medications
for migraine treatment.
Diagnosis may be difficult because of the variety of
symptoms that can occur and their similarity to symp-
toms displayed with anxiety or pain. Extra-pyramidal
symptoms are severely distressing for patients. Patients
who have experienced inadequately treated dystonia or
akathisia commonly refuse to use these drugs in the
future, with the result that an important therapeutic
option is lost.
Diagnosis
Neuroleptic-induced dystonia and akathisia.
Tip
Neuroleptic medications are useful for severe
headaches, but clinicians should be careful not to
misinterpret the extra-pyramidal side effects of dys-
tonia or akathisia as being due to anxiety or pain
and mistakenly treat the patient with additional
neuroleptics.
A woman with intractable headache
and vomiting
Case
While on call, a physician received a message to con-
tact a patient. This 36-year-old woman had a long
history of occasional migraine headaches that usu-
ally responded well to 10 mg of oral rizatriptan. The
109
 Chapter 7: Errors in management of acute headache
previous day she had developed a typical headache, but
she was getting over a bout of norovirus and could not
keep rizatriptan down. Her headache had lasted almost
two days and she wanted to know if she should go to
the ED.
When should someone with a bad headache
go to the emergency department?
Even patients with a well-established history of pri-
mary headaches such as migraine can have other
causes of headache. An ED visit is appropriate when
there are “red flag” signs or symptoms that sug-
gest a dangerous cause of headache. These include a
headache that is unusually severe or sudden in onset –
the so-called “thunderclap” headache – or headaches
associated with fever or confusion. In this case, the
patient reported that her headache was a typical one
for her – what was unusual was that nausea prevented
her from taking her usual oral medication. When ques-
tioned further she denied high fever, confusion, or any
other alarm symptoms. She preferred to avoid a trip
to the ED if possible. She was there several years ago
under similar circumstances and ended up having a
CT scan of her head and a lumbar puncture, compli-
cated by a severe post-lumbar puncture headache that
did not resolve until she had a blood patch.
What strategy might be helpful in treating
this headache, and prevent similar
situations in the future?
Migraine is a chronic illness. Even patients whose
headaches typically respond to oral treatment are likely
to have occasional headaches that do not. Sometimes
the headache begins while they are sleeping and has
progressed to the point of vomiting when they awaken.
Perhaps treatment has been delayed if a headache
developed when they were without medication. Or
perhaps, as in this case, circumstances made it impos-
sible to use customary treatment. Whatever the reason,
a number of useful backup or “rescue” treatments may
still be effective even when a patient’s first-line treat-
ment has failed. Often these will prevent the need for
an ED visit.
As a general rule, rescue treatments should be
non-oral. Non-oral treatments take effect quickly and
will still be effective in patients who are vomit-
ing. Table 7.4 lists common rescue treatments. They
110
Table 7.4. Commonly used rescue therapies
Triptans:
– Sumatriptan SC 4–6 mg
NSAIDs:
– Indomethacin 50 mg PO or PR (PR may be more effective)
– Ketorolac nasal spray/PO 15–30 mg
Sedating phenothiazines:
– Promethazine 25 mg PO
– Prochlorperazine 5–10 mg PO or 25 mg PR (PR may be more
effective)
Ergot derivatives:
– Dihydroergotamine nasal spray 0.5 mg, 1 spray each nostril q15
min ×2
Steroids:
– Prednisone, dexamethaxone, or methylprednisolone
Used with caution due to concern of overuse or addiction
syndromes:
– Butalbital-containing medications
– Narcotics
PO, by mouth; PR, per rectum; SC, subcutaneous
include injectable medications such as sumatriptan,
which comes in an auto-injector that can be self-
administered, nasal sprays, and rectal suppositories. In
the latter category, we find promethazine suppositories
to be particularly useful. They will usually stop vomit-
ing and put a patient to sleep until a headache runs its
course.
Discussion
Poorly controlled pain is an acceptable reason to go
to the ED, but many patients with headache dislike
seeking ED care. They report feeling labeled as “drug
seekers” by medical staff, and dislike the long wait-
ing times. Most also dread the fluorescent lights and
loud, busy environment of the ED. Then, too, there is
the danger of excessive diagnostic testing or investiga-
tion as ED staff seek to “rule out” dangerous causes of
headache such as subarachnoid hemorrhage. Finally,
patients who visit the ED with a bad headache are at
risk of receiving nonspecific treatments such as nar-
cotics, which may create expectations of future nar-
cotic treatment that are difficult to reverse. In our expe-
rience, it is difficult to predict with certainty when or
whether patients with well-controlled migraine might
need to visit the ED for an out-of-control headache.
We find it prudent to provide a backup “plan B” rescue
treatment for every patient, even those who think they
might not need it. Our advice is to “fill the prescription
 Chapter 7: Errors in management of acute headache

and keep it in your medicine cabinet. You may never Table 7.5. Selected treatments for status migrainosus
need it, but if you do you will be glad it is there.” Drug and dose Comments
Dihydroergotamine (DHE) Pretreatment with an
Diagnosis 0.5–1 mg IV as a single dose/
1 mg IV q8 hours ×3 days:
antiemetic such as
metoclopramide is advisable.
Migraine in the setting of recent gastrointestinal this is often referred to as Patients may need to be
illness. the “DHE protocol” or admitted or treated in an
“Raskinizing” a patient (since outpatient infusion center in
Dr. Neil Raskin first devised order to receive the full DHE
this protocol) protocol
Tip Droperidol 2.5 mg IV every Patients should be warned of
Most headache patients benefit from having a “rescue” 30 minutes until three doses possible side effects of sedation
plan for backup treatment when their first-line strate- or patient is completely or and akathisia. Use is limited
gies fail. In most cases this backup treatment should be almost headache-free because of the potential for
prolongation of the QT interval
non-oral so that it will be effective even if the patient
Metoclopramide 10 mg IV Monitor for dystonic reactions
is vomiting.
Prochlorperazine 5–10 mg IV Monitor for hypotension,
sedation, and dystonic reactions
A never-ending migraine
Case ments. In status migrainosus, the ongoing episodes are
A 29-year-old woman presented to the ED with a typical of a patient’s previous migraine attacks, differ-
severe headache. This was her second visit to the ED ing only in duration. Sometimes, as in this case, an
in four days for the same problem. She had a long his- attack may be long-lasting because vomiting interferes
tory of intermittent migraine without aura that usu- with the ability to treat the headache, but even patients
ally responded well to oral almotriptan. A week prior who use parenteral therapies will sometimes have par-
to this visit she had developed a typical headache, but ticularly stubborn attacks of migraine.
her usual treatment was not effective, perhaps because There are no large studies of treatments for sta-
she was vomiting and could not keep the medicine tus migrainosus. Status migrainosus is usually treated
down. After three days of severe headache and persis- with parenteral medication in order to maximize
tent vomiting, she presented to the ED. bioavailability of the drug. Intravenous hydration is
Her neurologic examination was normal, and a CT also helpful to counteract the volume depletion that
scan of the head and lumbar puncture were also nor- may arise after several days of poor appetite or vom-
mal. She was treated with subcutaneous sumatriptan iting. Drugs with longer durations of action are pre-
and intravenous hydration, and the headache resolved. ferred to treat this long-lasting form of migraine. (Of
She returned home, but the headache and vomiting note, the patient in this vignette received subcuta-
recurred. The headache was bilateral, throbbing, asso- neous sumatriptan, which has a half-life of only a
ciated with phono and photophobia, and worse with few hours.) Table 7.5 lists some treatment regimens
movement. She rated her pain 10 on a 0–10 scale. Her commonly recommended for the treatment of status
neurologic examination was normal. migrainosus in the acute setting. Dihydroergotamine
(DHE) is especially useful and the “DHE protocol” of
What is this patient’s diagnosis and how repetitive parenteral administration of DHE-45 is an
especially valuable strategy. Droperidol has also been
should it be treated? employed with substantial clinical success, but its use
Migraine episodes that continue for at least three days is limited by the potential for prolongation of the QT
are termed status migrainosus. Temporary improve- interval.
ment with medication or interruption during sleep is
disregarded in determining the duration of an attack. How could migraine recurrence and return
Status migrainosus is considered a complication of
migraine. Recurrence of migraine depends on many to the ED have been prevented?
things, including the patient’s age, sex, the initial sever- About half of patients who receive ED treatment for
ity of the headache, and the choice and timing of treat- migraine will experience headache recurrence within

111
 Chapter 7: Errors in management of acute headache
the next few days. Some, as the patient in this vignette,
will return to the ED because of relapse. Several meta-
analyses have evaluated clinical trials studying the
use of steroids, mostly dexamethasone, as a treat-
ment that will reduce headache recurrence. The way
in which steroids might reduce the risk of headache
recurrence is not clear, but may relate to suppres-
sion of neurogenic inflammation. There appear to be
few adverse events associated with single doses of
dexamethasone.
Discussion
Even patients whose migraines are well controlled will
occasionally have headaches that do not respond well
to treatment and which last beyond 72 hours. A single
dose of dexamethasone is well tolerated and is mod-
erately effective in preventing migraine relapse. One
meta-analysis estimated a number needed to treat of
9. Because steroids take some time to become effec-
tive, they are not usually used as stand-alone treatment
in the ED. In fact, there is little evidence to suggest
that steroids are an effective symptomatic treatment.
Rather, they are used in addition to standard abortive
therapy for the attack.
Steroids are typically given intravenously under
these circumstances, although one study suggested
that oral treatment might also be effective. Doses in
clinical trials have ranged from 10 to 24 mg IV, but
higher doses (ࣙ 15 mg of dexamethasone) appear to
be most effective. For this reason, and because there
are few adverse events associated with a one-time dose
of dexamethasone, we recommend that a dose of at
least 15 mg should be used. The importance of dose
is underscored by a recent study that used just 10 mg
of IV dexamethasone to treat status migrainosus in
the ED, and did not find an effect compared with
placebo.
Diagnosis
Status migrainosus.
Tip
The addition of a high dose (ࣙ 15 mg IV) of dexam-
ethasone to customary ED migraine treatment pre-
vents headache recurrence with a number needed to
treat of 9.
112
A man with cluster headache and
limited sumatriptan access
Case
A 36-year-old man was referred for consultation
because of headaches that awoke him from sleep nearly
every night. The headaches were located behind the
right eye and were described as sharp and stabbing.
They lasted about an hour and were rated 10 on a 0–10
pain scale. With the pain, he had mild nausea and a
stuffy nose on the side of the headache. The headaches
occurred daily for the last month. He had a similar
bout of headaches last fall that resolved after three
months. His primary care physician diagnosed cluster
headache, gave him a prescription for the sumatrip-
tan auto-injector (4 mg), and arranged for him to have
oxygen to use at home. The patient reported that suma-
triptan was effective for the headaches but his insur-
ance would only pay for only four boxes (eight doses)
a month. He could not afford to pay for it out of pocket.
He had tried the oxygen but said that it “doesn’t do
much and those nasal prongs hurt my nose.”
The patient had not been started on preventive
treatment to reduce the number of attacks he was expe-
riencing. Since he had a history of bipolar disorder
with previous episodes of mania requiring hospitaliza-
tion, steroids were avoided but treatment with 240 mg
of sustained release verapamil daily was started.
Was this patient receiving optimal
treatment for individual attacks of
headache?
Subcutaneous sumatriptan is approved by the FDA for
treatment of cluster headache attacks. It can be self-
administered with a reusable auto-injector. Individual
cartridges containing the medication are inserted into
the auto-injector and discarded after use. When the
drug was first introduced the auto-injector cartridges
were only available in a 6 mg “one size fits all” dose.
Since the daily dose limit for sumatriptan is 12 mg
a day, that meant patients could use just two injec-
tions in a 24-hour period. For patients with cluster
headache, who can have more than two attacks in a
24-hour period, two injections a day are sometimes
not sufficient to treat all headaches. Additionally, the
6 mg dose produced unpleasant side effects in some
patients.
 Chapter 7: Errors in management of acute headache

For these reasons, cartridges that contain only 4 Table 7.6. Selected studies of oxygen for treatment of
individual attacks of cluster headache
mg of the drug have been introduced. This lower dose
of subcutaneous sumatriptan is useful in a number Flow rate and
of clinical settings, although some patients still need method of
the full 6 mg dose. In this patient’s case, however, the Citation administration Results
4 mg dose reportedly worked well, so his sumatriptan Kudrow L. Response of 6 liters/minute via Oxygen aborted
treatment does appear to be optimized. It should be cluster headache attacks face mask for more than 7/10
to oxygen inhalation. 15 minutes attacks in 82%
noted that parenteral sumatriptan can also be adminis- Headache. 1981;21:1–4. of patients
tered using a “needle-less” system that propels the drug Anthony M. Treatment 8 liters/minute via 100% oxygen
through the skin using a blast of air. This system can of attacks of cluster face mask for was effective in
only deliver a 6 mg dose, however, and in our experi- headache with oxygen 15 minutes relieving pain in
inhalation. Clin Exp all 12 patients
ence is more expensive than the original auto-injector. Neurol. 1981;18:195. studied
The patient’s description of “nasal prongs” when
Fogan L. Treatment of 6 liters/minute via 56% of patients
asked about his oxygen treatment, however, suggested cluster headache. A face mask for 15 had relief of
that oxygen is not being used correctly. Incorrect oxy- double-blind minutes headache in
gen administration – too low a flow rate, use of nasal comparison of oxygen v. over 80% of
air inhalation. Arch attacks
prongs instead of a face mask, or both – is probably the Neurol. 1985;42:362–3.
cause of apparent lack of benefit in this patient’s case.
Cohen AS, Burns B, 12 liters/minute 78% of patients
When administered by face mask at a high rate of flow, Goadsby PJ. High-flow via face mask for had complete
oxygen therapy is highly effective for treatment of indi- oxygen for treatment of 15 minutes or substantial
vidual attacks of cluster headache. This patient should cluster headache. JAMA. pain relief at
2009;302:2451–7. 15 minutes
be encouraged to repeat a trial of 100% oxygen at
12 liters/minute administered via face mask for
15 minutes at the onset of headaches. using a mask at a flow rate of 7 liters/minute for
15 minutes) with sublingual ergotamine. Oxygen
How does oxygen work to abort an attack of aborted more than seven out of ten attacks in 82% of
the patients. Ergotamine worked in 70% of patients but
cluster headache? the response time for oxygen was faster, on average
The way in which oxygen works to stop an attack of 6 minutes. Two small subsequent studies also reported
cluster headache is not known. A number of theo- good results using flow rates of 6 and 8 liters/minute.
ries have been advanced, including the possibility that A larger, carefully done study used 100% oxygen at a
oxygen inhibits firing of trigeminal afferent neurons, rate of 12 liters/minute for 15 minutes. At 15 minutes
affects the parasympathetic pathway, or decreases cere- after treatment 78% of patients were pain-free or had
bral blood flow through vasoconstrictive mechanisms. substantial pain relief, compared with only 20% who
Some experts have postulated that there is a hypersen- received high flow air placebo. These studies are sum-
sitivity to oxygen in cluster headache. marized in Table 7.6. To summarize, high flow 100%
oxygen administered at 12 liters/minute for 15 minutes
at onset of an attack with a nonrebreather face mask
Discussion should be prescribed.
The first clear description of cluster headache was pro-
vided by the English physician Wilfred Harris. He
accurately described many features of the disorder, Diagnosis
including the characteristic Horner’s syndrome. The Episodic cluster headache.
first systematic study of oxygen for cluster headache
was done by Dr. Lee Kudrow, himself a cluster
headache sufferer. He was reportedly prompted to Tip
investigate oxygen because of an account of its ben- Oxygen is an effective, evidence-based therapy for
efits by an optometrist with cluster headache who acute attacks of cluster headache, but high flow admin-
used it to abort his own attacks. Kudrow’s study com- istration through a nonrebreather mask is important to
pared self-administered 100% oxygen (administered avoid treatment failure.

113
 Chapter 7: Errors in management of acute headache
A woman with migraine planning to
attempt pregnancy
Case
A 30-year-old woman with a history of episodic
migraine with aura presented for a routine follow-up
visit to the headache clinic. At that visit, she told the
physician that she was having headaches about three
times a month and sumatriptan was reliably effective
within an hour or so. She sometimes took metoclo-
pramide for nausea. She was planning to try to con-
ceive in the next six months, but wanted to know
what options for treatment would be available. Her
migraines were debilitating before she was started on
sumatriptan, and she was concerned about missing
work if she was unable to take the drug when she had
headaches.
What options are available for treating her
migraines during pregnancy?
Management of headache during pregnancy ideally
starts even before pregnancy is attempted, when non-
pharmacologic techniques such as biofeedback can be
started. Lifestyle modifications such as regular meals,
adequate hydration, regular sleep, and stress man-
agement can also be very helpful in decreasing the
frequency of headache. If pharmacologic treatment
is required, acetaminophen is first-line symptomatic
therapy and several antiemetics are commonly used in
pregnancy. Metoclopramide and ondansetron have an
FDA safety in pregnancy rating of B (more on FDA rat-
ings below). If these treatments are ineffective, other
commonly used options include butalbital-containing
medications and opiates, though these are both FDA
Category C. Steroids such as prednisone or dexam-
ethasone can also be used. Occipital nerve blocks are a
low-risk procedural intervention. Conservative treat-
ments are usually initiated first, and treatments with
greater risk are added only if necessary.
Can she take sumatriptan?
Although controlled trials have not been performed,
the limited available information regarding safety
of sumatriptan in pregnancy is reassuring. In the
population-based Norwegian Mother and Child
Cohort Study, 1535 women had taken triptans during
pregnancy. There was no significant association
114
Table 7.7. FDA use-in-pregnancy safety categories
Category A: Controlled human studies show no risk
Category B: No evidence of risk in humans but there are no
controlled human studies
Category C: Risk to humans has not been ruled out
Category D: Positive evidence of risk in humans
Category X: Contraindicated in pregnancy
between triptan use in the first trimester and major
congenital malformations or other adverse preg-
nancy outcomes. Triptan use in the second or third
trimester was associated with a slightly increased
risk of atonic uterus and blood loss during labor. A
registry for sumatriptan and naratriptan sponsored
by the manufacturer included 599 women, most of
whom had taken sumatriptan. Although this was
a small sample size, the number of birth defects in
this group was comparable to that in the general
population. Because of these studies, some headache
specialists feel comfortable prescribing sumatriptan
to patients whose headaches are not controlled by the
therapies discussed above. While this clinical scenario
arises rarely in our practice, we do keep this on the
list of options for pregnant patients with otherwise
intractable headaches.
Discussion
The FDA categorizes safety of medications during
pregnancy into Categories A, B, C, D, and X (Table
7.7). Category A indicates the best evidence of safety,
and is limited to drugs for which there are controlled
human studies showing no risk. Category X indi-
cates that a medication is contraindicated in preg-
nancy due to a clear risk of serious harm to the fetus.
There are alternative systems for evaluating the safety
of the medication during pregnancy, including the
TERIS risk rating and narrative reports from propri-
etary databases such as REPROTox. The frequent dis-
agreement and inconsistencies among these systems
illustrates how difficult it can be to make determina-
tions based on the limited data available.
Table 7.8 lists the FDA use-in-pregnancy rat-
ings for commonly used symptomatic treatments of
migraine in pregnancy. Acetaminophen is perhaps
the most commonly used due to its B rating, but all
of the antiemetics also have a long track record of
safety. In fact, all of the antiemetics except ondansetron
have received a TERIS rating indicating that after

Table 7.8. FDA use-in-pregnancy ratings of commonly used
symptomatic therapies for migraine
Analgesics
Acetaminophen B
Aspirin and NSAIDs C (D in the third trimester)
Butalbital C distress, the benefits of using pharmacologic therapy
Caffeine C may be felt to outweigh the potential risks. This con-
Codeine C
Hydrocodone/acetaminophen C
(APAP)
Meperidine C is discussed in greater detail in Chapter 8. Although
Oxycodone C
All triptans C
Antiemetics
Metoclopramide B
Ondansetron B to attempt pregnancy should have a treatment plan for
Promethazine C any headaches that do occur.
Prochlorperazine C
Chlorpromazine C
exposure during gestation, teratogenic risk is unlikely
on the basis of evidence rated at least fair to good. As
described above, there is so far no evidence suggesting
teratogenicity associated with the use of sumatriptan.
Ergots should be avoided because they decrease uter-
ine blood flow. NSAIDs are also typically avoided dur-
ing the first trimester, due to increased risk of spon-
taneous abortion, and third trimetester, due to risk of
premature closure of the ductus arteriosus and renal
abnormalities.
Despite the availability of symptomatic med-
ications generally regarded as safe during preg-
nancy, nonpharmacologic therapy is the mainstay of
acute headache treatment during pregnancy. Thermal
biofeedback, relaxation training, and physical therapy
are all effective. It may be helpful to start training in
these therapies prior to attempting pregnancy, so that
they are available when needed particularly during the
first trimester. In addition, the importance of hydra-
tion should not be underestimated. Sometimes, IV flu-
ids and resting in a dark quiet room are all that is
needed to help a pregnant migraineur feel significantly
better.
In developing a treatment plan, physicians should
realize that the use of pharmacologic therapy to man-
age migraines during pregnancy is best based on
balancing the harms and benefits for an individual
patient. The FDA package inserts for most medications
state that use of the medication in pregnancy is not
recommended unless “benefit outweighs risk.” Medi-
cations are not tested on pregnant women during clin-
ical trials, so clear data about medication safety during
Chapter 7: Errors in management of acute headache
pregnancy are often lacking and rely on postmarket-
ing registries or observational data. In patients whose
migraines are severe, lead to frequent protracted vom-
iting and dehydration, or cause significant emotional
versation should be documented in the chart.
The natural history of migraine during pregnancy
migraine typically improves during pregnancy, it does
not always do so and often does not improve until after
the first trimester. For this reason, all patients planning
Diagnosis
Episodic migraine without aura, planned pregnancy.
Tip
Many migraine treatments are contraindicated in
pregnancy, but several medications with a long track
record of safety are available. Patients should be reas-
sured that treatments are available if headaches persist
past the first trimester.
Treatment of headache during
lactation
Case
The patient in the previous case had her baby and
returned for follow-up. Her migraines had improved
during the second half of the pregnancy, but they had
recurred postpartum. She was having them about three
days a week, and they seemed to be the same headaches
that she had before she was pregnant. She thought
the increased frequency might be related to disrupted
sleep and the stress of returning to work. For treatment
of acute headaches she was still using acetaminophen,
which she had taken during during pregnancy, but this
was not consistently effective.
How is medication safety during lactation
determined?
The American Academy of Pediatrics (AAP) Com-
mittee on Drugs has provided a non-exhaustive list
of medications, grouped into the following categories:
usually compatible with breast-feeding; effects are
115
 Chapter 7: Errors in management of acute headache

unknown but may be of concern; require temporary Table 7.9. Medication safety during lactation
cessation of breast-feeding; associated with significant Medications usually Medications Medications
effects on some infants and should be given with cau- compatible with associated for which
tion; contraindicated. This list was last updated in breast-feeding with significant safety during
2001. Another commonly used resource is Hale’s Med- (Hale rating is in effects/give lactation is
ications and Mothers’ Milk, which is updated every two parentheses where with caution unknown/may
years. These ratings are based on large-scale clinical available) during lactation be of concern
observations or controlled trials. Safety is rated L1–L5, Propranolol (L2) Aspirin Amitriptyline (L2)
with L1 indicating the safest drugs and L5 indicating Magnesium Atenolol Nortriptyline
Riboflavin Ergotamine SSRIs
those which are contraindicated during lactation. Valproate (L2) Lithium
Verapamil (L2)
Steroids
What medications can be recommended to Acetaminophen
Ibuprofen (L1)
treat this patient’s headaches while she is Ketorolac
Indomethacin
breast-feeding? Naproxen (L3)
Good options for symptomatic therapy during lacta- Simple opioids
Sumatriptan (L3)
tion include acetaminophen, NSAIDs, and sumatrip-
tan. Eletriptan is not listed in the AAP rating system,
but has a Hale rating of L2. Steroids, including dexa-
of headaches postpartum, and another study showing
methasone and prednisone, are usually compatible
with breast-feeding. None of the antiemetics have been that breast-feeding had a protective effect. At the very
least, it is safe to say that migraine is not a contraindi-
rated using the AAP rubric. Importantly, aspirin and
cation to breast-feeding.
ergots should be avoided.
In this case, the patient was started on propra- Because the mechanism of transmission of a med-
ication to the infant during lactation is different from
nolol for preventative therapy and had reduction of
the mechanism of transmission to a fetus during preg-
headaches to once per week. Minor headaches were
treated with ibuprofen and the more severe headaches nancy, the medication safety ratings of drugs may
differ depending upon whether they are used dur-
occurring about twice per month were treated with
sumatriptan. The excretion of maternally ingested ing pregnancy or during breast-feeding. Valproate, for
drugs into breast milk is determined by a number of example, has a class X safety rating during pregnancy
(positive evidence of risk in human or animal stud-
factors, including their lipophilicity. The amount of
maternally ingested sumatriptan that is excreted into ies) but is listed as “usually compatible” with breast-
breast milk is negligible; that fact in conjunction with feeding in the AAP rating system and has a Hale’s L2
rating.
the short half-life of the drug means that it is a good
choice for treatment of acute migraine in women who Likewise, some medications perceived to be safe
are breast-feeding. Some women choose to pump and during pregnancy are contraindicated during lacta-
tion, although this is less common. One important
discard breast milk for a period of time after ingesting
medications, but that is not medically necessary when example of this is nadolol, which is probably safe when
used in pregnancy, but is lipophilic and thus con-
sumatriptan is used.
centrated in breast milk. Case reports exist of several
infants who experienced heart block when breast-fed
Discussion by a mother taking this drug.
The postpartum period is a time when many women Several factors determine medication safety during
with migraine experience increased headache fre- lactation, including the amount excreted into breast
quency. In this case, the patient identified two com- milk, the concentration of drug in the mother, and the
mon triggers for increased frequency of migraine: dis- amount of milk ingested by the infant. Table 7.9 lists a
rupted sleep and increased psychologic stress. There selection of medications often used during lactation,
is conflicting information about the effect of lactation along with their safety ratings. In general, there are
itself on migraine frequency, with one study suggest- fewer contraindications to migraine treatments during
ing that breast-feeding did not change the frequency breast-feeding then during pregnancy.

116

If women remain concerned about exposing an
infant to a specific medication, there are strategies
to reduce further the infant’s potential exposure. For
example, the mother can take the medication just after
she has breast-fed her infant or just before the infant is
likely to have an extended sleep period. If the mother is
willing to express milk, she can pump and discard the
breast milk after taking the medication in question, the
so-called “pump and dump” method.
Diagnosis
Episodic migraine without aura in a breast-feeding
woman.
Tip
The safety profile of the same drug may differ depend-
ing upon whether it is used when a woman is preg-
nant or when she is breast-feeding. A number of med-
ications can be safely used to treat headaches when
women are breast-feeding, so there is no need for a
woman to avoid lactation in order to treat headaches.
Further reading
Optimizing triptan use
Burstein R, Collins B, Jakubowski M. Defeating migraine
pain with triptans: a race against the development of
cutaneous allodynia. Ann Neurol. 2004;55:19–26.
Dodick DW. Triptan nonresponder studies: implications
for clinical practice. Headache. 2005;45:156–62.
Tfelt-Hansen P. Maximum effect of triptans in migraine? A
comment. Cephalalgia. 2008;28:767–8.
Triptan sensations
Dodick D, Lipton RB, Martin V, et al. Consensus statement:
cardiovascular safety profile of triptans (5-HT agonists)
in the acute treatment of migraine. Headache. 2004;
44(5):414–25.
Papademetriou V. Cardiovascular risk assessment and
triptans. Headache. 2004;44(Suppl 1):S31–9.
Visser WH, Jaspers NM, de Vriend RH, Ferrari MD.
Chest symptoms after sumatriptan: a two-year clinical
practice review in 735 consecutive migraine patients.
Cephalalgia. 1996;16(8):554–9.
Triptans, SSRIs, and serotonin syndrome
Evans RW, Tepper SJ, Shapiro RE, Sun-Edelstein C, Tietjen
GE. The FDA alert on serotonin syndrome with use of
Chapter 7: Errors in management of acute headache
triptans combined with selective serotonin reuptake
inhibitors or selective serotonin-norepinephrine
reuptake inhibitors: American Headache Society
position paper. Headache. 2010;50(6):1089–99.
Shapiro RE, Tepper SJ. The serotonin syndrome, triptans,
and the potential for drug-drug interactions. Headache.
2007;47(2):266–9.
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 Chapter
Pitfalls in drug therapy to prevent
8 headaches
Decisions about preventive treatment for chronic
headache problems are focused on answering the ques-
tions of when, which, how, and for how long. That
is, when should preventive treatment be considered,
which drug should be used, how should it be given,
and for how long should therapy be continued? There
is no single best answer to each of these questions, but
there are some principles that can help guide decisions.
These are listed in Table 8.1. Cases in this chapter illus-
trate the pitfalls that can be encountered in trying to
optimize preventive drug therapy in some commonly
encountered and challenging situations.
The major primary headache disorders of mi-
graine, tension-type headache, and cluster headache
occur in both episodic and chronic varieties. At
either end of the frequency spectrum decisions about
whether to use preventive treatment are relatively
simple, but when headache frequency is variable or
intermediate it can be difficult to know whether to rec-
ommend preventive therapy.
Decisions about which drug to use are also com-
plicated. As several cases in this chapter illustrate, the
choice of a particular preventive treatment depends
heavily upon individual patient circumstances and
concomitant illnesses. A particularly thorny problem
in clinical practice is how to approach patients who
have “tried everything.” Is it ever appropriate to con-
clude that preventive treatment is ineffective? Treat-
ment guidelines issued by authoritative groups such as
Table 8.1. When to consider migraine prevention
r Three or more headache episodes per week
r Significant interference of headache with daily activity
r Acute medications ineffective, contraindicated, or overused
r Adverse effects from acute medications
r Patient preference for prevention
r Associated comorbidities: e.g. depression, anxiety,
hypertension, insomnia
r Special circumstances: elderly, pregnant, pediatric populations
the American Headache Society (AHS) and American
Academy of Neurology (ANN) categorize preventive
medications according to the quantity and strength
of scientific evidence supporting their use, but apply-
ing this in an individual patient’s case may not be
simple.
A man with frequent headaches who
does not want daily medicine
Case
A 36-year-old man had a long history of episodic
migraine without aura. He had a good response to
sumatriptan but his physician was worried that he was
using it too frequently. Two months after a follow-
up visit at which he had received a prescription for
18 100 mg sumatriptan tablets with five refills, the
patient called to request more sumatriptan. He said he
was about to go on vacation, had used all of his recent
prescription plus refills, and did not want to be with-
out it and risk a headache while abroad. The physician
approved a one-time refill of nine tablets, but asked
the patient to come in for an appointment when he
returned from vacation.
At that visit the physician told the patient that
sumatriptan had not been studied for long-term daily
use and that frequent use could paradoxically make
headaches worse and lead to medication overuse
headache. He recommended that the patient consider
taking a daily medication to cut down on the frequency
of his headaches. The patient admitted that he was tak-
ing sumatriptan “at least” three or four days a week, but
said that it was working well and he had no side effects
from it. Furthermore, he often had three or four days
each week without headache. He did not like the idea
of taking medication every day to treat a problem that
was not daily.
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Table 8.2. Risk factors for the development of chronic

Was the physician right to urge the use of headache
preventive medication for migraine? Risk factor Comments
There are several reasons to believe that the physician Female sex Not modifiable
in this case was right in urging this patient to consider Baseline headache frequency Potentially modifiable with
preventive therapy. This patient’s pattern of frequent preventive medication that
headache and excessive use of symptomatic medica- reduces headache frequency.
Evidence is lacking to show
tion for headache was not a recent development. The that this has a long-term
physician had long been worried about how much favorable impact on the
medication the patient was taking. If anything, the natural history of headache
patient was probably underestimating his headache Overuse of medications to Modifiable
frequency, since he used 90 tablets of sumatriptan over treat acute headache
a 60-day period. In these circumstances most doctors Obesity Modifiable; preliminary
would have suspected medication overuse and prob- observational evidence
suggests possible benefit of
ably would have discussed preventive treatment with weight loss on headache
the patient earlier. In hindsight, this case also high- frequency in migraine
lights the importance of keeping track of headache fre- Stressful life events Modifiable through changes
quency and medication use through headache diaries, in environment and training
in stress reduction and
more frequent office visits, or even pill counts. coping techniques
It seems safe to assume that the patient’s true
Depression Modifiable through drug or
headache frequency corresponded to at least 6–14 other treatments
headache days per month. Patients in this interme-
Snoring Modifiable if snoring is related
diate frequency category are at high risk of devel- to upper airway problems or
oping even more frequent headaches over time. In produces sleep apnea
the Frequent Headache Epidemiology Study, such Excessive caffeine Modifiable
patients were followed for a year. The risk of develop- consumption
ing chronic headaches over that period was strongly Based on information from Scher AI, Stewart WF, Ricci JA, Lipton
related to baseline headache frequency. The risk of RB. Factors associated with the onset and remission of chronic
daily headache in a population-based study. Pain. 2003;106:81–
chronic headache increased exponentially at around 9.
one headache per week.
Based on this evidence, we discuss the use of pro-
phylactic treatment for headaches once a patient with
migraine or tension-type headache begins regularly headache frequency. These are listed in Table 8.2.
having one or more headaches a week. This does not Although headache sufferers with these characteris-
mean that everyone who has one headache a week tics were more likely to develop chronic headache, it
must be on preventive treatment. Rather, it means that remains unclear whether the relationship is causal. In
the use of preventive treatment should be considered. other words, it is not clear whether being obese or
If a patient’s headache frequency or medication use experiencing stressful life events caused headaches to
seems to be inexorably trending upwards, this is a nat- become chronic or whether some underlying factor
ural point at which to consider the institution of pre- was associated with both events. Because of this it is
ventive therapy. uncertain whether addressing the factors that can be
modified will alter the natural history of headache.
There are, however, other important medical rea-
Is daily medication the only thing that sons to address many of these risk factors, and emerg-
might reduce the risk of chronic migraine for ing evidence indicates that at least some of them
may be causally related to the development of chronic
this patient? headache. For example, several small studies have
The Frequent Headache Epidemiology Study identi- shown improvement in headache frequency in patients
fied a number of other risk factors for the devel- with chronic migraine who have lost weight following
opment of chronic headache in addition to baseline bariatric surgery.

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As outlined in Table 8.2, risk factor modification
can include recommendations to lose weight, per-
form regular physical exercise, learn relaxation tech-
niques, maintain normal body weight, use treatments
to reduce headache frequency, and treat snoring or
sleep apnea if present.
Discussion
Patients at the low end of the headache frequency spec-
trum have occasional headaches that are widely dis-
persed in time. They usually prefer and benefit from
treatment directed to individual attacks of headache.
Most are reluctant to consider taking medication every
day to cope with a problem that is intermittent. This is
understandable, since even the best preventive drugs
for migraine do not prevent all attacks, and most
are associated with unintended adverse events. These
range from minor nuisances to potentially serious or
permanent problems. The trade-offs – slightly fewer
headache days a month in exchange for a daily side
effect – may not seem worth it to patients.
In contrast, patients with high frequency head-
aches have daily or near-daily headache. In most cases,
they should strongly consider the use of preventive
headache treatment. Even if an analgesic or triptan
treatment for individual attacks works well, those
drugs are not intended to be used on a daily basis. Too-
frequent use of medications intended to treat indi-
vidual episodes of headache can produce serious side
effects such as gastric ulceration with nonsteroidal
anti-inflammatory drugs, or tolerance or addiction in
the case of barbiturate- or opioid-containing medica-
tions. Additionally, most drugs used to treat individ-
ual attacks of headache are also suspected of produc-
ing medication overuse headache when used too often.
Decisions about whether preventive treatment is war-
ranted can be difficult to make when patients report
an intermediate headache frequency. In such situations
it is useful for patients to keep an objective record
of headache frequency in the form of a headache
diary. That helps both patients and doctors identify the
point at which headache frequency is so consistently
high that it no longer makes sense to treat headaches
individually.
Diagnosis
High frequency episodic migraine.
Chapter 8: Pitfalls in preventive drug therapy
Tip
Patients with an intermediate frequency of headache
should be closely monitored for excessive medication
use and an increase in the number of headaches. The
option of preventive therapy should be discussed once
headache frequency is approximately once a week.
Selecting preventive treatment for
a patient who has never used it
Case
A 27-year-old woman had been followed for sev-
eral years with a diagnosis of migraine with typical
visual aura. She was otherwise healthy and on no
medications. Although triptans were effective for her
headaches, she did not tolerate them because of un-
pleasant “triptan sensations” and fatigue. Fortunately,
her individual headache attacks usually responded
well to a combination of 10 mg of metoclopramide and
1000 mg of aspirin.
At a recent visit, however, her diaries showed that
her headache frequency had gradually increased over
the last year from an average of three headaches a
month to six or seven attacks. Some attacks lasted sev-
eral days and she was missing work because of them.
She had recently gone to the emergency department
for a headache that lasted three days.
Her neurologic and physical examination was nor-
mal. She had tried to reduce headache triggers such
as erratic sleep patterns, caffeine use, and stress but
had not been able to decrease her headache frequency.
Because her doctor warned her about medication
overuse headache, she had been careful not to use
her abortive migraine treatment more often than two
days a week. Instead, she had “toughed things out” but
noted that “maybe that’s how I ended up in the ED.”
What does this patient’s clinical course
suggest and what treatment would you
recommend?
This patient had experienced a steady, gradual increase
in headache frequency, severity, and duration. She
was experiencing disability as a result of headaches
and is worried about losing her job. She had six
or seven attacks of migraine a month, some lasting
several days at a time. Her headache frequency was
thus close to the cutoff of 15 days a month used to
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Table 8.3. Summary of the 2012 American Headache Society and American Academy of Neurology treatment guidelines for the
preventive treatment of episodic migraine
Level A: Established as effective
Should be offered to patients requiring migraine prophylaxis
Drug Dose examples Common side effects or problems
Divalproex/sodium valproate* 500–1000 mg/day Known cause of birth defects; weight gain, fatigue
Metoprolol 47.5–200 mg/day Fatigue, hypotension
Petasites (Butterbur) 50–75 mg bid Classified as a nutritional supplement and not subject to
the same level of FDA oversight or scrutiny
Propranolol* 120–240 mg/day Fatigue, hypotension
Timolol* 10–15 mg bid Fatigue, hypotension
Topiramate* 25–200 mg/day Paresthesias, cognitive impairment, acute angle-closure
glaucoma, renal stones
Level B: Probably effective
Should be considered for patients requiring migraine prophylaxis
Drug Dose examples Common side effects or problems
Amitriptyline 25–150 mg/day Fatigue, dry mouth, weight gain
Fenoprofen 200–600 mg tid Gastrointestinal side effects, platelet inhibition
Feverfew 50–300 mg bid; 2.08–18.75 mg tid for Classified as a nutritional supplement and not subject to
MIG-99 preparation the same level of FDA oversight or scrutiny
Histamine 1–10 ng subcutaneously twice a
week
Ibuprofen 200 mg bid Gastrointestinal side effects, platelet inhibition
Ketoprofen 50 mg tid Gastrointestinal side effects, platelet inhibition
Magnesium 600 mg trimagnesium dicitrate qd Diarrhea
Naproxen/naproxen sodium 500–1100 mg/day for naproxen; 550 Gastrointestinal side effects
mg bid for naproxen sodium
Riboflavin 400 mg/day Classified as a nutritional supplement (vitamin) and not
subject to the same level of FDA oversight or scrutiny
Venlafaxine 150 mg extended release/day Agitation
Level C: Possibly effective
May be considered for patients requiring migraine prophylaxis
Drug Dose examples Common side effects or problems
Candesartan 16 mg/day Hypotension
Carbamazepine 600 mg/day Fatigue, cognitive impairment, allergic reaction
Clonidine 0.75–0.15 mg/day; patch Hypotension
formulations also studied
Lisinopril 10–20 mg/day Nonproductive cough, hypotension
Nebivolol 5 mg/day Fatigue, hypotension
Pindolol 10 mg/day Fatigue, hypotension
Flurbiprofen 200 mg/day Gastrointestinal side effects, platelet inhibition
Mefanamic acid 500 mg tid Gastrointestinal side effects, platelet inhibition
Coenzyme Q10 100 mg tid Classified as a nutritional supplement and not subject to
the same level of FDA oversight or scrutiny
Cyproheptadine 4 mg/day Fatigue, dry mouth, weight gain
* FDA approved for migraine prevention.

122

distinguish episodic from chronic migraine. This pat-
tern of gradually increasing headaches over time was
consistent with the development of chronic migraine
and is sometimes called “chronification.” Further-
more, this patient had attempted to address lifestyle
and other trigger factors that might have been con-
tributing to her headache. She also had none of the
potentially modifiable risk factors listed in Table 8.2.
This is a situation in which the use of preventive treat-
ment for migraine should be strongly considered. Her
physician suggested that she consider the use of pre-
ventive treatment for migraine and prescribed dival-
proex sodium 250 mg twice daily, stating that this
drug was US Food and Drug Administration (FDA)
approved for migraine prevention and therefore a
good treatment choice.
What are the choices for preventive
treatment of migraine, and how do you
choose among them?
Table 8.3 summarizes medications that have shown
evidence of benefit in preventing migraine attacks. The
evidence is best for Level A drugs, less strong for Level
B drugs, and suggestive but least compelling for Level
C drugs. Not all drugs with a high level of evidence are
FDA approved for migraine prevention, which might
be a factor in choosing a drug. Nondrug preventive
treatments for migraine and other headache disor-
ders are covered in Chapter 9, but several (such as
biofeedback-assisted relaxation) have good evidence
of benefit and could also be considered for this patient.
The choice of preventive treatment is often based
on a patient’s comorbid conditions or other med-
ications. For example, in a patient with concomi-
tant hypertension, a beta-blocker such as propranolol
would be a good choice for migraine prevention.
The patient described in this case had no other med-
ical problems that might benefit from a particular
drug, but she is already using aspirin for treatment
of individual headaches. Thus, a nonsteroidal anti-
inflammatory drug such as ibuprofen, ketoprofen,
fenoprofen, or naproxen would not have been a desir-
able choice for preventive treatment.
The patient in this case returned three months later
for a follow-up visit. Her headache diary showed a
clear improvement in headache frequency, but she had
gained 8 pounds and was concerned about weight gain:
“I’m hungry all the time.” She asked whether there
Chapter 8: Pitfalls in preventive drug therapy
Table 8.4. Weight gain as a side effect of migraine preventive
drugs
Associated with Associated with
weight increase Weight neutral weight loss
Beta-blockers Lisinopril, Protriptyline
candesartan
Divalproex sodium Riboflavin (vitamin Topiramate
B2)
Most tricyclic Venlafaxine
antidepressants
were other treatments that would help her headaches
without producing weight gain.
Which preventive medications are less likely
to produce weight gain or other undesirable
side effects?
Patient preference for specific migraine drugs and
adherence to treatment regimens is strongly influ-
enced by drug side effect profiles. Certain adverse
events, such as weight gain or reproductive toxicity, are
particularly undesirable for young women, the group
of migraine patients most likely to need preventive
treatment for migraine. Unfortunately, weight gain is
a common side effect of many migraine preventive
treatments.
The association between migraine and weight is
complex. There is no evidence that overweight or obe-
sity increases the risk of developing migraine in the
first place. In people who already have migraine, how-
ever, overweight and obesity are associated with an
increased risk of migraine progression. Migraine is
not, however, clearly associated with an elevated risk
for becoming overweight or obese, at least in women.
Divalproex sodium is not only associated with
weight gain, but is also a known cause of birth defects.
It should be used with caution in women of reproduc-
tive potential, especially when there are other alterna-
tives. It was probably not the optimal choice of preven-
tive treatment for this patient.
Are there treatment choices that would reconcile
the patient’s desire to avoid weight gain with the physi-
cian’s desire to use a Level A drug that is FDA approved
for migraine prevention? Table 8.4 lists migraine drugs
that are associated with weight gain, weight loss, or
are “weight neutral.” Only topiramate has Level A evi-
dence supporting its use, is not associated with weight
gain, and is FDA approved for migraine treatment. It
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 Chapter 8: Pitfalls in preventive drug therapy
may increase the risk of facial clefts in infants exposed
during pregnancy, so this patient should be cautioned
to use effective birth control measures.
Discussion
Specific patient factors should be taken into account
in choosing preventive medication. Although it is gen-
erally preferable to start with drugs that have a high
level of scientific evidence for their use, the side effect
profiles of the drugs and patient preference should be
considered.
Diagnosis
High frequency episodic migraine with typical visual
aura.
Tip
Even drugs that are FDA approved for migraine pre-
vention and rated Level A in treatment guidelines
may be the wrong treatment choice for an individual
patient. The optimal choice of preventive treatment
for migraine requires a comprehensive assessment of
comorbid medical conditions, patient side effect pref-
erences, and the strength of evidence for each drug.
Preventive treatment for a patient
who has “tried everything”
Case
A 38-year-old woman sought treatment for headaches
she had experienced for years. She had received a diag-
nosis of chronic migraine. Following a careful his-
tory, review of her previous testing results, and phys-
ical examination her new physician concurred with
that diagnosis. The patient had completed a written
headache history form required by the practice. This
showed that she has tried most typically used preven-
tive and abortive treatments for migraine. When asked
whether any had been helpful, she said she couldn’t
recall exactly, but then remarked that some of them
“helped a little bit but obviously they weren’t that good
or I would still be on them.” She was interested in pur-
suing nondrug approaches to headache, and asked if
she was a candidate for the new “migraine surgery” she
had read about in the newspaper.
124
Do you agree that this patient is refractory
to commonly used migraine preventive
medications?
While it is certainly possible that this patient is
refractory to pharmacologic preventive treatment for
migraine, the information she has provided is not suf-
ficient to be certain. It is clear what drugs have been
tried, but there is no information about the doses that
were used or the duration of the treatment trials. It is
also not clear what the patient means by “helped a lit-
tle bit.” For all of these reasons, it is not obvious that
this patient with chronic migraine is truly treatment-
refractory or that previous treatment trials have been
inadequate.
Her new physician requested her previous treat-
ment records and reconstructed her treatment history.
This showed that while she had tried many of the typi-
cally used treatments for migraine, the doses used were
uniformly subtherapeutic and the treatments were
continued for only a few weeks before being discon-
tinued. For example, the patient was treated for just
three weeks with a dose of 20 mg of propranolol twice
a day before it was discontinued and another medica-
tion begun. The physician suggested to the patient that
the next step in her treatment was to retry some typ-
ical migraine preventive drugs, this time making sure
to aim for the target dose of medication and continue
each drug for two to three months. She also asked the
patient to keep a careful record of her daily pain level
in order to quantify any response to treatment.
How could the need for retrials of
medication have been prevented?
There are only a limited number of therapies with
good evidence of benefit for migraine prevention. It
is important to make sure each drug selected is given
a careful therapeutic trial. Meticulous, systematic
regimens of treatment ensure that drugs are used
appropriately and given every chance to work. This is
important before concluding that one or all of them
are ineffective.
It is very discouraging for patients to be told that
they need to go back and retry medications that pre-
viously seemed ineffective, yet this is necessary when
those drugs have not been used correctly. Adequate
patient preparation for such trials is important. Before
embarking on preventive treatment, we explore patient

Table 8.5. Principles of migraine prevention
r Choose preventive medications with comorbid conditions in
mind
r Start with a low dose and increase slowly to target dose
r Continue target dose for at least 2 to 3 months
r Monitor with calendar or diary: goal is a 30–50% reduction in
frequency or reduced intensity/use of abortive medication
r Consider combinations of preventive treatments in refractory
r
patients
Consider tapering or discontinuing medication after 4 to 6
months of good headache control
expectations about the benefits of preventive treat-
ment. Many have unrealistic ideas about how effective
these treatments are, and expect that they will quickly
eliminate all headaches. We educate patients that the
goal for preventive therapy is to reduce, not eliminate,
headaches. We also stress that the treatment may take
several months to become effective, and that the dose
of medication may need adjustment. We emphasize the
need to keep a headache calendar in order to identify
the effects of treatment, since patient global recall of
drug effectiveness is unreliable. The success of preven-
tive therapy can be enhanced by adherence to several
principles of treatment (Table 8.5).
Discussion
Treatment guidelines can aid in the choice of which
preventive medication to use. Even in the best of cir-
cumstances most pharmacologic treatments to prevent
migraine reduce the frequency of migraine attacks
by about half. In some cases preventive therapy does
not necessarily reduce headache frequency but instead
makes individual headaches milder or improves the
patient’s response to abortive treatment. These modest
benefits can be difficult to identify in a disorder like
migraine which naturally waxes and wanes.
Then, too, most preventive drugs do not take effect
immediately. It can be a month or two before treatment
response is apparent. The dose of medication required
to suppress headaches also varies from patient to
patient; many of the drugs are commonly started at
low doses in order to improve tolerability. If patients
discontinue use before the target dose is achieved,
the drug may appear to be ineffective. Thus, two or
three months of treatment at a drug’s target dose (or
the highest tolerated dose) should be required before
drawing conclusions about treatment benefits.
Diagnosis
Chronic migraine.
Chapter 8: Pitfalls in preventive drug therapy
Tip
In a patient with apparent treatment-refractory head-
aches, it is important to verify that previous treatment
trials have been of adequate dose and duration.
Another patient who has tried
everything
Case
A 30-year-old female with a family history of migraine
and a past history of menstrual-related migraine
sought treatment for a two- to three-year history of dis-
abling chronic migraine. Multiple treatments through-
out her 20s had failed to produce improvement in her
headaches, but she had found that with exercise and
maintenance of a low stress level she could control her
symptoms.
In her late 20s she began a stress-filled job in
her family’s large antiques business and experienced
an increase in migraine frequency to 20 days per
month. She was treated sequentially with amitripty-
line, divalproex sodium, topiramate, verapamil, pro-
pranolol, venlafaxine, sertraline, and indomethacin.
These drugs failed to provide meaningful improve-
ment in headache frequency or severity. Onabo-
tulinumtoxinA injections initially appeared to reduce
the number of headache days per month to 15, but that
improvement was not sustained.
The patient treated individual headaches with
sumatriptan, which was partially effective, but her use
of that drug was limited by insurance restrictions on
the number of tablets she could get each month. The
patient continued aerobic exercise but her headaches
remained poorly controlled and her previous physi-
cian had told her that there was nothing more that
could be done. He suggested that the patient reduce her
work hours or quit her job.
Has this patient tried everything, and
should she quit her job?
The patient’s income was important to her family, so
she hoped to avoid limiting or stopping work. Her
disappointing response to previous prophylactic ther-
apy is not unusual. Most preventive medications for
migraine have modest benefits at best, and the bench-
mark for considering a drug trial a success is a 50%
125
 Chapter 8: Pitfalls in preventive drug therapy
reduction in headache frequency in 50% of subjects.
Some patients do not achieve even this level of success,
however. Thus, many patients in primary and specialty
care report that they have “tried everything” to pre-
vent headaches and have failed to benefit from treat-
ment. In some cases previous treatment trials were of
inadequate duration or a subtherapeutic dose of med-
ication was used, and retrials of monotherapy must be
pursued. Once the physician is satisfied that previous
attempts at prophylaxis have been adequate, however,
it is reasonable to consider using combinations of pre-
ventive medications.
Combination treatment or “rational polyphar-
macy” is the standard of care for other intractable ill-
nesses such as treatment-resistant depression or hyper-
tension, so it makes sense that it should also be used in
refractory headache problems. When chosen carefully,
combination treatment strategies may target different,
complementary underlying causes of headache. As a
general rule, drugs from the same therapeutic class
should generally not be combined because of the risk
of synergistic side effects. Rarely, some combinations
can have serious side effects. The combination of dival-
proex sodium and topiramate, for example, has been
reported to cause encephalopathy.
Combination therapy may also be wise in patients
with multiple medical conditions such as depression
and headache. Finally, combination therapy may allow
the use of lower drug doses and reduce the chance of
troublesome side effects. For example, a patient whose
headaches are only controlled on a high dose of beta-
blockers that produces fatigue might benefit from a
lower dose of the drug in combination with a small
dose of a tricyclic antidepressant.
How firm is the evidence supporting the use
of combinations of preventive treatments
for headache?
One disadvantage of combination therapy is the lack
of evidence from clinical trials to inform treatment
choices. Table 8.6 summarizes some commonly used
combination treatments and the rationale for their use.
Given the wide possible variety of different drug com-
binations and the small number of studies, there is
insufficient evidence to evaluate the benefit of many
treatment combinations. However, there is evidence of
added benefit from the combination of nonpharmaco-
logic therapies with some pharmacologic treatments.
126
Table 8.6. Some commonly used combinations of preventive
treatments for migraine
Combination Comments
Tricyclic anti- Patients who do not tolerate a full
depressant plus a dose of either drug alone may do
beta-blocker well on a combination of these two
drugs in low or moderate doses
Topiramate plus Topiramate may counteract mild
beta-blocker weight gain that can be seen with
beta-blockers
Topiramate plus Topiramate may counteract the
antidepressant sometimes substantial weight gain
that can be seen with tricyclic
antidepressants
Beta-blocker plus Different side effect profiles may
divalproex sodium improve tolerability
Beta-blocker plus This combination of medications
other anti- generally does not produce
depressants, e.g. synergistic side effects
venlafaxine
Drug therapy plus There is substantial evidence that the
nondrug therapy combination of drug therapy (e.g.
amitriptyline) and relaxation training
is superior to either treatment alone
OnabotulinumtoxinA OnabotulinumtoxinA generally does
injections with any not produce systemic side effects so
drug or nondrug it is a good choice for combination
therapy therapy in patients with chronic
migraine who have failed
monotherapy. Note: it is only
approved for prevention of chronic,
not episodic, migraine
There is also evidence about at least one combina-
tion of treatments that does not work. A recent trial
examined the benefits of adding long-acting propra-
nolol 240 mg/day to topiramate 50–100 mg/day in
patients with chronic migraine (average of 15 or more
days of headache a month). There was no statistically
significant difference between the two groups in treat-
ment response: those in the combination group expe-
rienced an average drop of 4 headache days per month
compared with 4.5 days per month in the group that
received topiramate alone.
Since the superiority of some treatment combina-
tions has been demonstrated in clinical trials, and since
such treatments are commonly used in clinical prac-
tice, it is clearly important to conduct additional stud-
ies to examine this treatment strategy.
The successful therapeutic strategy for the patient
in this case ultimately turned out to be a com-
bination of four preventive drugs: amitriptyline,
topiramate, venlafaxine, and onabotulinumtoxinA

injections. Although the use of this many drugs in
combination is unusual, it is sometimes necessary in
patients with particularly refractory headaches. After
six months on this therapy the patient was able to
work full time without missing multiple days and was
no longer overusing medication to treat individual
headache attacks.
Discussion
The goal of combination therapy for prevention of
headaches is better pain relief or fewer side effects or
both. Ideally, the pain-reducing effects of the combi-
nation will be additive or even synergistic while side
effects will not be. Combining treatments can increase
the risk of adverse events, but this problem can be min-
imized by choosing the drugs carefully and by careful
monitoring and adjustment of doses.
Diagnosis
Chronic migraine refractory to monotherapeutic pre-
ventive medications.
Tip
Before concluding that a patient has failed preven-
tive treatment for migraine, combinations of preven-
tive agents should be tried.
Preventive treatment in a patient with
multiple medical conditions
Case
A 58-year-old woman sought treatment for headaches
that started when she was a teenager. Until her late 20s,
headaches occurred once a month, usually a few days
before the onset of menstrual bleeding. They met diag-
nostic criteria for migraine. In her 30s the headaches
increased in frequency. She was started on propranolol
and headaches decreased to once a month. The drug
was stopped a year later. In her early 40s the patient had
developed rheumatoid arthritis. Despite treatment
with nonsteroidal anti-inflammatory drugs, the con-
dition progressed and she was treated with hydroxy-
chloroquine and methotrexate. The patient also
developed Raynaud’s phenomenon, insomnia, and
hypertension. Her blood pressure was well controlled
on a thiazide diuretic but she had recently been
switched to prazosin and given trazadone to help with
sleep.
Chapter 8: Pitfalls in preventive drug therapy
She reported that her headaches had again in-
creased in frequency and were occurring twice a week.
They still met criteria for migraine and her neuro-
logic examination was normal. Her blood pressure was
142/92 mm Hg and she had changes consistent with
rheumatoid arthritis on examination.
Are the patient’s new medications or her
elevated blood pressure producing
headache?
The relationship of mild, chronic hypertension to
headache is still debated, but most experts believe that
modest elevations in blood pressure are unlikely to
produce headache. Sudden, abrupt elevations in blood
pressure, however, can certainly provoke headache.
Such “malignant hypertension” is caused by severely
elevated blood pressure and is associated with signs of
end-organ damage. Malignant hypertension can occur
with preeclampsia, cocaine intoxication, pheochro-
mocytoma, following severe head injury, or a num-
ber of other conditions. Papilledema usually should
be present to make a diagnosis of malignant hyper-
tension, and the blood pressure is usually above
220/120 mm Hg.
In this case the patient’s blood pressure is well
below that associated with urgent or emergent levels
of hypertension. She has a long-standing history of
headaches that occurred even when her blood pressure
was well controlled. It is not very likely that her blood
pressure is contributing to her current headache prob-
lem, but her blood pressure treatment might be con-
tributing to her headache problem. She was recently
switched from a thiazide diuretic to prazosin. Pra-
zosin is a postsynaptic alpha-adrenergic blocker that
can cause substantial vasodilation, especially when
it is first begun. Medications with strong vasodila-
tory effects commonly appear on lists of medica-
tions thought to aggravate or precipitate migraine. The
patient has also recently been started on trazodone,
another drug often identified as possibly aggravating
pre-existing headache problems.
How do the patient’s comorbid conditions
affect the choice of treatment for her
migraines?
Most drugs used for headache prevention were
initially developed to treat other conditions, and
their beneficial effects on headache were discovered
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 Chapter 8: Pitfalls in preventive drug therapy
serendipitously. In some cases the multiple effects of
these treatments can be exploited to treat more than
one condition with a single drug. For this patient, a
calcium channel blocker such as verapamil could be
considered as a way to treat three of the patient’s med-
ical problems: hypertension, migraine, and Raynaud’s
phenomenon. Updated treatment guidelines from the
AAN and the AHS reviewed clinical trial evidence for
the use of verapamil in the prevention of migraine, and
concluded it was insufficient to make a recommenda-
tion for or against the use of the drug. Clinical experi-
ence, however, suggests there is a place for this drug
in selected patients such as the one in this vignette,
who stands to benefit on several fronts if treatment is
successful.
On the other hand, vasoconstrictive medications
such as triptans, ergotamine, dihydroergotamine, or
isometheptene-containing compounds should prob-
ably be avoided in this patient, because they can
elevate blood pressure. Hypertension should be well
controlled before the use of these drugs is consid-
ered. Although the beta-blocker propranolol was pre-
viously effective for this patient’s migraine, it is not
a good treatment choice now that she has developed
Raynaud’s phenomenon.
Discussion
Headache that coexists with other medical complaints
can be challenging to manage. Headache can be aggra-
vated or caused by a wide variety of conditions that
include rheumatologic conditions such as systemic
lupus erythematosus or giant cell arteritis. In this
patient, however, the headaches preceded the onset of
rheumatoid arthritis by many years, suggesting no link
between the two conditions. Similarly, her hyperten-
sion was not severe and was a long-standing condi-
tion. Her headaches had fluctuated in severity inde-
pendently of her blood pressure control, suggesting
that her mild hypertension was an unlikely explana-
tion for her current headache exacerbation.
Many medications are suspected of causing or
aggravating headaches. Patients with pre-existing
headache disorders, such as the patient in this case, are
probably most susceptible to this side effect. Vasodila-
tors such as nifedipine, prazosin, and nitrates are prob-
ably the most common offenders. A careful review
of this patient’s medications suggested that the recent
switch to prazosin might be responsible for both
an increase in her headaches, perhaps related to its
128
vasodilating properties, and also for a decline in the
control of her hypertension. The medication was dis-
continued and she was switched to verapamil, ulti-
mately reaching a dose of 120 mg/day. Trazodone was
replaced with melatonin. Her headaches decreased to
her usual frequency of once a month, and her blood
pressure and Raynaud’s phenomenon were under good
control.
Diagnosis
Migraine with superimposed headache attributed to
medication.
Tip
In patients with headache and other medical condi-
tions, it is important to determine whether the medical
complaints are independent of the headache or related
in some way, since headache can be an early manifes-
tation of many diseases.
A woman on migraine prophylaxis who
wants to become pregnant
Case
A 24-year-old woman with a history of frequent dis-
abling migraines presented to a headache clinic to dis-
cuss the management of migraines during pregnancy.
Her headaches had previously been under good con-
trol on a combination of propranolol and riboflavin
for preventive therapy and she used sumatriptan to
treat individual headache attacks. Her doctor had told
her that she should be off all medications for several
months before she tried to become pregnant. He also
suggested that her migraines might be a contraindica-
tion to pregnancy. The patient wanted to have a child
but was afraid that if she stopped her medications as
recommended her headaches would be much worse
and that she would be without treatment.
What is known about the effect of
pregnancy on migraine, and does migraine
increase the risk of poor pregnancy
outcomes?
For most women with migraine, the news about preg-
nancy is good. Studies consistently show that about
70% of women with migraine experience some degree

of improvement during pregnancy. This is most notice-
able during the second and third trimesters and is most
likely in women who do not have aura. Not all women
improve, however: some experience no change in their
headaches and a minority find that their headaches are
worse. Some women with aura find that aura frequency
and complexity may increase.
Migraine without aura does not appear to increase
the risk of pregnancy complications or poor outcomes.
Migraine with aura, however, is associated with an ele-
vated risk of a number of pregnancy complications,
including preeclampsia and peripartum stroke. Thus,
women who have migraine with aura should be moni-
tored carefully for the development of these problems.
A particular clinical challenge is distinguishing wors-
ening of migraine from an early case of preeclampsia,
where headache can be an early and only symptom of
the disorder.
What options are available for preventive
treatment of migraine during pregnancy?
Most women with migraine are highly motivated to
minimize the use of any medications during preg-
nancy, and they commonly try to limit medication
use to individual attacks of headache. Appropriate
abortive treatments for acute migraine are discussed in
Chapter 7. If at all possible, it is desirable to avoid the
use of preventive medication during the first trimester
of pregnancy when most organogenesis is occurring.
If headaches have not improved by the end of the first
trimester this is a natural time at which to consider
starting preventive treatment.
Table 8.7 lists commonly used migraine preven-
tive medications and their FDA use-in-pregnancy rat-
ings. For both topiramate and divalproex sodium there
is good quality evidence of potential fetal risks. Top-
iramate is associated with orofacial clefts and dival-
proex with neural tube defects and cognitive deficits.
Ergot derivatives such as methergine, angiotensin-
converting enzyme inhibitors, and angiotensin recep-
tor blockers should also be avoided in women who
plan to become pregnant or who are not using effec-
tive birth control methods. The majority of commonly
used migraine preventives are Category C drugs.
These ratings, however, do not always take clinical
experience into account. For example, beta-blockers
are in Category C (except atenolol, which is pregnancy
Category D) yet have a long history of safe use dur-
ing pregnancy. Because it has good evidence of efficacy,
Chapter 8: Pitfalls in preventive drug therapy
Table 8.7. FDA use-in-pregnancy ratings for commonly used
migraine preventive drugs*
FDA use-in-pregnancy
Agent rating
Amitriptyline C
Botulinum toxin C
Gabapentin C
Nortriptyline Not assessed
Propranolol C
Topiramate D
Valproate (divalproex sodium) X for treatment of migraine
Verapamil C
Steroids C
* FDA use-in-pregnancy ratings: Category A: controlled human
studies show no risk; Category B: no evidence of risk in humans
but there are no controlled human studies; Category C: risk to
humans has not been ruled out; Category D: positive evidence
of risk in human or animal studies; Category X: contraindicated
in pregnancy.
propranolol is therefore often considered the optimal
choice when migraine preventive treatment is needed
during pregnancy. In contrast, the clinical trial and
other scientific evidence of efficacy is not as strong for
many of the other “C” drugs, so it is more difficult to
assess the balance of benefits and harms. We gener-
ally avoid the use of preventive medications that do
not have substantial evidence of benefit for migraine.
While it might be defensible to try such treatments
in nonpregnant patients, the stakes are higher during
pregnancy and we prefer to stick with Level A or Level
B treatments (as rated in the 2012 AHS/AAN migraine
prevention guidelines).
What about natural treatments such as
herbs and vitamins or behavioral
treatments? Are these safe to use in
pregnancy?
Biofeedback-assisted relaxation therapy has good evi-
dence of benefit for the prevention of migraine. Phys-
ical therapy is less well studied but likely to be safe.
We generally encourage women with migraine who are
planning pregnancy to consider learning biofeedback
techniques prior to pregnancy so they are “on board”
during the first trimester. In addition, the importance
of staying well rested and well hydrated and min-
imizing daily stress should not be underestimated.
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 Chapter 8: Pitfalls in preventive drug therapy
Worsening headaches can sometimes be effectively
managed if patients cut back on home or work respon-
sibilities.
Some preventive treatments for migraine are herbs
or nutritional supplements. These are typically used
in very large, supraphysiologic doses. These drugs are
not subject to the same level of FDA scrutiny as pre-
scription pharmaceuticals, and since they are pur-
chased without a prescription patients do not interact
with pharmacists. A worrying study done a number of
years ago had researchers posing as pregnant women
inquire at health food stores about “safe” treatments
for headache and nausea. A surprisingly large propor-
tion of women were advised by store workers to use
products that are not recommended for use during
pregnancy or that are known to be unsafe in preg-
nancy. Patients may assume that these “natural” treat-
ments are likely to be safer than prescription pharma-
ceuticals, but in fact the safety of these substances in
pregnancy is not known and we recommend they be
avoided for this reason.
How long do patients need to be off of
preventive medications before becoming
pregnant?
Patients often ask how long before attempting preg-
nancy they need to discontinue their migraine med-
ications, if medications are going to be discontinued.
There is no evidence that a prolonged waiting period
is required. The commonly used migraine preventive
drugs do not accumulate in the body so once they
have been stopped no meaningful fetal exposure will
occur. Because the maternal–fetal blood supply is not
connected until a week or so after fertilization, we
sometimes suggest that patients who are tracking ovu-
lation can take their medication until ovulation has
occurred.
The patient in this case decided to start
biofeedback-assisted relaxation training and gradually
reduce the doses of her preventive medications before
attempting pregnancy. If headaches were still trouble-
some at the end of her first trimester of pregnancy, she
planned to restart propranolol and use acetaminophen
to treat individual headaches.
Discussion
Migraine is highly prevalent during the reproductive
years, so the management of headache in pregnancy
130
is a common clinical challenge. Individually tailored
management of migraine during pregnancy, empha-
sizing nonpharmacologic options, is safe and effec-
tive for many patients. Most patients with migraine
cope well with pregnancy and are able to manage
their headaches. Poor pregnancy outcomes are not
common, so there is no good reason to discourage
patients in good health from undertaking pregnancy.
Given the epidemiology of migraine, the management
of headache in the setting of pregnancy is a common
occurrence.
Women with migraine should be encouraged to
plan their pregnancies and to come for a precon-
ception visit prior to attempting pregnancy. This is
a useful opportunity to discuss a pregnancy treat-
ment plan for headaches and to educate patients about
the effects of pregnancy on migraine. It is also good
practice to recommend that all women of childbear-
ing potential take a multivitamin with folate, which
has been shown to reduce the risk of neural tube
defects.
In developing a migraine treatment plan for preg-
nancy, physicians and patients should weigh the poten-
tial benefits of treatment against known harms, tak-
ing an individual patient’s situation into consideration.
This is not always easy, since medications are not tested
in pregnant women and data about pregnancy effects
are thus sparse and imperfect, often based on post-
marketing registry surveillance studies or other obser-
vational data. Certainly for women whose migraines
are severe and lead to frequent protracted vomiting
and dehydration, or cause significant emotional dis-
tress, the benefits of using pharmacologic therapy will
usually be judged to outweigh the potential risks.
Conversations about the harms and benefits of treat-
ments during pregnancy should be documented in the
patient’s chart.
Diagnosis
Episodic migraine without aura; preconception
planning.
Tip
Women with migraine should not be discouraged from
attempting pregnancy and long medication-free inter-
vals are not needed prior to pregnancy. Most women
with migraine will be able to manage headaches during
pregnancy and will have good pregnancy outcomes.

A middle-aged woman with chronic
migraine and paresthesias
Case
A 39-year-old woman returned for a follow-up visit
for migraine. She had a lengthy history of chronic
migraine as well as asthma, Type II diabetes melli-
tus, hypothyroidism, Factor V Leiden deficiency, and
a strong family history of venous thromboembolism.
Her headaches had always been difficult to control.
During her early 30s she had frequently missed work
because of them. Eventually headaches improved on
a combination of topiramate (50 mg twice daily) and
propranolol (60 mg a day).
The patient did well for several years on this combi-
nation treatment. Two months before her current visit
she underwent left shoulder manipulation and steroid
injections in her elbow under anesthesia. She awoke
from the surgery with shortness of breath and severe
pain under her left breast. She was eventually diag-
nosed with an embolus in the left main pulmonary
artery and was admitted to the hospital for anticoag-
ulation and monitoring.
In the hospital, propranolol was discontinued
because of low blood pressure. The patient’s hospi-
tal stay was prolonged by the development of bilat-
eral upper and lower extremity paresthesias. Topira-
mate was dismissed as a possible cause because the
patient had been on the same dose of the drug for years
without any problems. A neurology consultant iden-
tified no clear explanation for the paresthesias. Nerve
conduction studies were performed and her doctors
considered discontinuing her warfarin in order to per-
form electromyography (EMG) but ultimately decided
against it. The patient asks you whether she should
have an EMG.
What was the most likely cause of this
patient’s paresthesias?
This patient did have diabetes, a condition that
can produce paresthesias and neuropathy, but it is
unlikely that diabetic neuropathy and paresthesias
would present so suddenly. Despite the fact that this
patient had been on topiramate for years without
troubling side effects, topiramate was the most likely
cause for her bilateral paresthesias. When this was
reviewed with the patient, she recalled that prior to
her recent illness she had not always remembered to
Chapter 8: Pitfalls in preventive drug therapy
take her topiramate regularly and “might have missed
some doses.” In the hospital she received the medica-
tion as prescribed. After discharge, because she paid
so much attention to taking her warfarin regularly,
her adherence to the prescribed regimen of topira-
mate remained excellent. This effectively increased the
amount of topiramate the patient was getting and
resulted in a side effect that had not occurred at lower
doses.
Paresthesias are the most common adverse
event with topiramate treatment. In clinical trials
for migraine, 47% of subjects randomized to the
100 mg/day dose of topiramate developed paresthesias
compared with just 5% of those receiving placebo, and
the risk of paresthesias was dose-related. In contrast,
concentration difficulties and memory impairment,
which are more widely recognized as topiramate side
effects, occurred in just 5% and 6% of topiramate
subjects, respectively, compared with 1% and 2% of
subjects who received placebo.
Most side effects of topiramate occur during titra-
tion. One study concluded that if adverse events have
not appeared after six weeks of treatment at a stable
dose of the drug, they are unlikely to occur. In this case,
however, the patient’s dose of medication was not sta-
ble when she developed paresthesias. It had effectively
been increased because of improved adherence to the
prescribed dosing regimen. Because this explanation
for her problem was so quickly discounted, the patient
almost underwent risky discontinuation of anticoagu-
lation in order to have an invasive procedure.
Can topiramate-associated paresthesias be
prevented or treated?
Starting with a low dose of topiramate, such as 25 mg
once daily, and working up slowly to the target
dose (usually 100 mg/day) may help minimize adverse
events and allow patients time to develop tolerance to
them. Paresthesias often improve over time. If they do
not, we find that many patients are willing to tolerate
them in exchange for improved control of migraines,
as long as they understand they are not dangerous and
will remit when the drug is stopped.
Anecdotal evidence suggests that potassium sup-
plementation may help reduce paresthesias. One
expert suggests the use of 20–40 mEq of potassium
chloride per day. Reducing the dose of the drug can
also be helpful, and patients sometimes find that
although a higher dose was needed to gain control
131
 Chapter 8: Pitfalls in preventive drug therapy
of headaches, a lower dose works well once control is
established. In some cases, however, a tolerable balance
between benefits and side effects cannot be found and
patients discontinue it.
A meta-analysis compared adverse drug events in
trials of topiramate for migraine with adverse events
in trials using the drug for epilepsy. The researchers
found that the adverse event profile of topiramate dif-
fered in the two conditions. Migraineurs were more
likely than subjects with epilepsy to experience a wide
range of side effects and more likely to drop out of
trials because of adverse events. For the 100 mg/day
dose of topiramate, the risk ratio for paresthesias in
migraineurs compared to epilepsy subjects was 2.7
(99% confidence interval: 1.80–3.97).
Discussion
This case reminds us that adherence to medications
can never be assumed. The patient in this case was a
nurse-practitioner and was certainly aware of the need
to take medications as prescribed. Even motivated
patients, however, find it difficult to take prescribed
medications regularly, and adherence decreases as the
number of daily doses increases.
Topiramate affects the activity of some types of glu-
atamate receptors, gamma-aminobutyric acid (GABA)
receptors, and voltage-gated sodium and calcium
channels. It is also a carbonic anhydrase inhibitor
and it is this pharmacologic effect that produces the
reversible paresthesias seen with topiramate and other
carbonic anhydrase inhibitors such as acetazolamide
and zonisamide. Some researchers have suggested that
the development of paresthesias is a favorable sign and
indicates an enhanced likelihood that migraine pro-
phylaxis will be successful.
Diagnosis
Chronic migraine; paresthesias due to topiramate.
Tip
When patients develop apparently new side effects
while on a previously tolerated medication, it is
worth exploring whether their compliance with rec-
ommended dosing has changed, or whether other
medications have been added or discontinued that
might affect the side effect profile.
132
Will preventive treatment work in a
patient who is overusing abortive
treatments?
Case
A 32-year-old man with chronic migraine was using
over-the-counter analgesics on a daily basis. He
reported that his headaches had gradually increased
over the years, and that he had responded by using
his prescribed and over-the-counter medications more
frequently. He was taking as many ibuprofen tablets
each day as allowed by the package instructions, along
with several tablets a day of a combination analgesic
containing acetaminophen, caffeine, and aspirin. He
obtained temporary relief with these treatments but
after an hour or so experienced the gradual return of a
dull headache. He also typically awoke in the morning
with a dull generalized headache.
The patient’s neurologist advised him that he
should be on preventive treatment for his headaches
but that preventive therapy for migraine would not
work while he was overusing short-acting medicines.
He suggested abrupt discontinuation of these medica-
tions, followed by a medication-free period of a month.
The doctor told the patient he probably had medica-
tion overuse headache and that it was important to see
if headaches improved when the overused medications
had been removed. The doctor told the patient that he
had done everything he could and that “the ball is in
your court.” The patient was afraid that he would be
unable to work if he discontinued his headache med-
ications. His doctor then said that he could offer no
further advice and the patient left care.
Does this patient have medication overuse
headache?
It can be difficult to distinguish chronic migraine
from medication overuse headache, but it seems
likely that medication overuse is contributing to this
patient’s pattern of chronic headaches. Medication
overuse occurs when a susceptible person uses exces-
sive amounts of symptomatic medication. Susceptibil-
ity to medication overuse headache probably varies,
and there are many patients in whom the develop-
ment of daily headache clearly precedes the medica-
tion use. With medication overuse headache, headache
severity and frequency and medication use increase in

lock-step, so that patients may feel they are trapped
in a never-ending cycle of more medication and more
headaches. This patient’s headaches have worsened in
close proximity to his increased use of medication.
The concept of medication overuse headache is
controversial, and diagnostic criteria change fre-
quently. Several clinical features, however, are useful
clues to the possibility that medication is making a
headache worse. First, the headache has either begun
or worsened substantially in the setting of daily or
near-daily use of analgesic medications such as trip-
tans, ergot derivatives, opioids, or combination anal-
gesics. (Nonsteroidal anti-inflammatory drugs are not
universally believed to produce medication overuse
headache.) Second, the headache usually improves and
sometimes even resolves when the offending medica-
tion is stopped. This latter criterion is particularly con-
troversial, however, since some experts suspect that
medication overuse can occasionally trigger an irre-
versible headache increase. We also find it useful to
inquire about whether headaches are present upon
awakening or waken a patient from sleep, which was
the case with this patient. Overnight is the longest
period of time many patients are without their med-
ication, and their rest is often disturbed by withdrawal
headache.
Is it always necessary to remove a
medication that is suspected of producing
medication overuse headache before
instituting preventive treatment of
migraine?
Clinical experience suggests that many patients who
are overusing symptomatic medication do obtain
benefit from migraine preventive medications. Once
headache frequency decreases, those patients may be
able to decrease their use of symptomatic medication
and experience substantial additional improvement in
headaches. This clinical impression has been bolstered
by several recent clinical trials in which even patients
who were overusing analgesic medications responded
to onabotulinumtoxinA or topiramate treatment for
chronic migraine.
While it is often desirable for a patient with refrac-
tory migraine to decrease the use of symptomatic med-
ication, the specifics of the clinical situation, as with
this patient, may make abrupt discontinuation imprac-
Chapter 8: Pitfalls in preventive drug therapy
tical. Additionally, abrupt discontinuation of certain
medications can produce a discontinuation syndrome
that is unpleasant or even dangerous: for example, too-
rapid elimination of barbiturate medications can pro-
voke seizures while abrupt opioid withdrawal may pro-
duce a flu-like syndrome. Before insisting upon “cold
turkey” and rapid withdrawal of symptomatic medica-
tions, we prefer to “meet patients half-way” by institut-
ing preventive therapy first followed by slow reduction
in the overused medication.
Discussion
Despite the fact that preventive medication may be
helpful even in patients who are overusing symp-
tomatic medications, it is still important to address
the problem of medication overuse. For some patients
preventive treatment will not be fully effective until
the problem of overuse has been addressed. The pro-
cess of medication reduction can sometimes be expe-
dited with the use of a burst and taper of steroids (e.g.
methylprednisolone) or (if an infusion center is avail-
able) with repetitive intravenous dihydroergotamine
given for several days during medication withdrawal.
Diagnosis
Medication overuse headache in the setting of chronic
migraine.
Tip
Abrupt discontinuation of overused symptomatic
medication is not always necessary to ensure response
to preventive treatment.
A woman on migraine treatment
who has a fall
Case
A 56-year-old woman was seen for evaluation of
headaches that had started in her early teens. The
headaches were unilateral, throbbing, and of severe
intensity, with associated nausea but no photo or
phonophobia. She did not experience aura. Headaches
typically lasted six to eight hours. They had occurred
roughly twice a month until about a year ago, when
headache frequency increased in the setting of a new,
more demanding job. She was experiencing two to
three headaches a week. Investigation, including an
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 Chapter 8: Pitfalls in preventive drug therapy
MRI scan of the head, had been normal. A variety of
migraine preventive treatments had been tried, includ-
ing propranolol, divalproex sodium, and topiramate,
but the patient had not tolerated them.
She reported that she was very sensitive to drug
side effects. On propranolol she was fatigued, on top-
iramate and divalproex she had memory problems,
and on amitriptyline she gained weight. Because the
patient was very worried about sedation, cognitive
impairment, and fatigue, she was given a prescription
for lisinopril, a drug that is typically not associated
with those adverse events.
Three weeks after beginning treatment with 10 mg
of lisinopril, the patient awoke in the middle of the
night and got out of bed to use the bathroom. She
stumbled and fell, sustaining a mild head trauma. In
the emergency department her blood pressure was
104/68 mm Hg. She was told that orthostatic hypoten-
sion from the lisinopril might have caused her fall and
was advised to stop the drug.
Was this patient’s fall caused by her
migraine treatment?
Many things, including tripping over furniture or a
rug, missing her footing in the dark, or even an acute
neurologic event, could have caused this patient’s fall.
Still, it is hard to ignore the temporal association
between the fall and the initiation of an antihyper-
tensive medication for migraine. The patient took her
once-daily dose of lisinopril at bedtime, so its maxi-
mal effect on blood pressure probably occurred dur-
ing the night. A syncopal or presyncopal event related
to orthostatic hypotension is therefore high on the list
of possible explanations for her fall. The patient in this
case did not recall any presyncopal symptoms because
she was groggy and sleepy.
Could this have been prevented?
Although the patient was started on a relatively low
dose of lisinopril, starting at even smaller doses might
be reasonable when there is a possibility of side effects.
Some patients, however, will forget to increase the dose
as instructed or will become impatient with a per-
ceived lack of effect at lower doses. They may prema-
turely discontinue therapy.
In our experience, though, most patients are able
to follow a simple titration schedule starting at a low
dose and increasing each week until the target dose is
134
reached. When the reasons for this “start low, go slow”
approach are explained, many patients are grateful that
the physician is attempting to prevent the develop-
ment of side effects (which are a significant concern
to patients who may be otherwise healthy). We have
learned the hard way, however, that any patient being
started on antihypertensive treatment for migraine
should be cautioned about the possibility of orthosta-
sis and presyncopal symptoms.
Rapid movement from lying to sitting or standing
is a common activity, but also a considerable physio-
logic stress. Syncope can occur with immediate, tran-
sient drops in blood pressure or from delayed ortho-
static hypotension, which can occur as late as 15 min-
utes after a change in posture.
The risk of orthostatic drops in blood pressure
appears to increase with age, so older patients should
be particularly cautioned to take care when getting out
of bed or rising quickly from a sitting position.
Discussion
Although antihypertensives are among the best tol-
erated migraine preventative medications, there are
several side effects that can limit use. As may have
occurred in this case, medication-related hypoten-
sion and bradycardia may contribute to symptomatic
orthostasis. Syncope or near syncope due to ortho-
static hypotension can affect patients of any age. The
side effects of orthostasis and bradycardia should be of
particular concern in older patients, who are at greater
risk for falls and for negative sequelae of falls.
Although syncope or presyncope is a side effect
with great potential for harm, antihypertensives can
also produce other adverse events. Exercise intoler-
ance may be seen with both beta-blockers and cal-
cium channel antagonists, although more commonly
with the former. Beta-blockers have been suspected
of aggravating depression, although this is controver-
sial. In any case, patients are likely to recognize this
if cautioned about the possibility ahead of time. Beta-
blockers also may worsen active asthma or Raynaud’s
disease. Calcium channel antagonists, on the other
hand, may produce constipation or pedal edema, as
well as generalized fatigue.
Although the phenomenon has not been systemat-
ically studied, we have found that many patients with
migraine are unusually susceptible to medication side
effects. In most patients, it is prudent to start pre-
ventive medications at quite low doses and increase

slowly as tolerated. For example, lisinopril could be
started at 5 mg nightly and increased to 10 mg after
a week. Propranolol could be started at 20 mg nightly,
and the dose then increased by 20 mg every week or
two if no side effects develop. This strategy of slow up-
titration is also recommended for patients with a his-
tory of childhood asthma. Verapamil can be started
at 40 mg nightly. Patients can also be asked to moni-
tor their blood pressure and heart rate between visits,
although they should be cautioned that this is to assess
for side effects and not for drug benefit. There is no
clear correlation between heart rate or blood pressure
and headache benefits.
Although some patients are unusually sensitive to
the side effects of antihypertensives, this reaction is
somewhat idiosyncratic. In fact, most patients with
low baseline blood pressure do very well when placed
on blood pressure medicines for the treatment of
migraine. Antihypertensives are frequently well toler-
ated by patients concerned about possible sedation or
cognitive side effects with other migraine preventives,
and are an important tool in the migraine armamen-
tarium. The key is to start low and go slow, advice com-
monly given when starting any medication for older
patients, but worth remembering for younger patients
as well.
Diagnosis
Migraine; orthostatic syncope possibly due to lisino-
pril.
Tip
Orthostatic hypotension is a possible complication
of migraine prophylaxis with antihypertensive drugs.
Susceptibility to this side effect may increase with age,
so starting with low doses and warning patients about
falls are important.
An older woman with blurry vision on
amitriptyline
Case
A 66-year-old woman with a long-standing history
of migraine without aura reported an increase in
headache frequency which she attributed to family
stress from her daughter’s divorce. She had begun to
care for her young grandchild, and described this as
“simultaneously delightful and stressful.” She asked
Chapter 8: Pitfalls in preventive drug therapy
about starting a preventive medication “to get me over
the hump” until she could adjust to the demands of
her new routine. She was healthy except for border-
line increased intraocular pressures, and her blood
pressure was 108/74 mm Hg. Her physician consid-
ered prescribing topiramate but knew that it might
raise intraocular pressures and precipitate glaucoma,
so instead he prescribed amitriptyline. The patient’s
headache decreased in frequency, but two months
later the physician received a call from the emer-
gency department. The patient had presented several
hours ago with acute bilateral loss of vision and eye
erythema. Ophthalmologic evaluation showed acute
angle-closure glaucoma.
What happened?
Topiramate is the migraine preventive most commonly
associated with increased intraocular pressure. Topi-
ramate may precipitate secondary acute angle-closure
glaucoma due to cilio-choroidal effusion, which dis-
places the lens and ciliary body. This can sometimes
be bilateral. It is less commonly realized that tricyclic
antidepressants or antipsychotic medications (such as
promethazine, which is sometimes used for headache-
associated vomiting) can also produce angle-closure
glaucoma.
The anticholinergic actions of tricyclic antidepres-
sants and some antipsychotic medications produce
mydriasis, which can precipitate angle closure in sus-
ceptible patients. Thus, all of these drugs should be
avoided in patients known to have narrow angles. In
contrast, patients with open-angle glaucoma are usu-
ally able to take these medications without adverse
events. Many patients are not aware of the difference
between the two types of glaucoma, so consultation
with the patient’s optometrist or ophthalmologist is
useful if either drug is considered for patients who
report a history of intraocular pressure abnormalities.
Discussion
Many medications used to prevent headaches can
occasionally be associated with ocular adverse events.
Lithium can produce eye irritation and keratoconjunc-
tivitis, probably because of effects on sodium trans-
port. In addition to producing angle-closure glaucoma
in predisposed patients, tricyclic antidepressants (and
even selective serotonin reuptake inhibitors [SSRIs])
cause mydriasis and accommodation problems that
may result in blurred vision. This is often transient.
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 Chapter 8: Pitfalls in preventive drug therapy
Ocular dystonias, eye movement disturbances and
changes in color or contrast discrimination have rarely
been associated with the use of topiramate or SSRIs.
Diagnosis
Acute angle-closure glaucoma from amitritpyline.
Tip
Potentially serious ocular complications are well rec-
ognized with topiramate therapy but can also occur
with other commonly used migraine preventive drugs,
particularly tricyclic antidepressants.
A woman with migraine worried about
the long-term safety of topiramate
Case
A 33-year-old woman presented to establish care with
a local neurologist after recently moving to the area.
She had a long-standing history of migraine without
aura and had been started on topiramate five years ago
by her previous headache specialist. Trials of several
other preventive treatments had not been successful,
but with topiramate her headaches decreased from a
frequency of three times a week to three times a month.
Her breakthrough headaches were effectively treated
with a triptan. She did not want to change her treat-
ment regimen, but she wanted to know if it was safe to
take topiramate long term.
What is known about the long-term risks of
chronic topiramate treatment?
Both cognitive side effects and paresthesias are com-
mon side effects of topiramate. They often lead to treat-
ment discontinuation, but they are entirely reversible.
Even the rare but feared complication of acute angle-
closure glaucoma usually resolves if the drug is dis-
continued promptly. The incidence of nephrolithiasis
in patients taking topiramate was approximately 1%
per year in clinical trials; thus, the cumulative risk
increases with duration of therapy but there is no evi-
dence that the risk of kidney stones persists after the
drug is stopped. In contrast, bone loss is painless and
insidious, and the pharmacologic profile of topiramate
does suggest that this may be an irreversible complica-
tion of long-term topiramate treatment.
136
Several lines of evidence suggest topiramate may
produce bone loss. Bone loss is a known complica-
tion of many antiepileptic drugs. The risk has been
best studied with older antiepileptic drugs such as
divalproex sodium. Less evidence has accumulated
about the risk of bone loss with newer antiepilep-
tic agents such as topiramate. However, a recent pilot
study evaluated biochemical and radiologic tests of
bone metabolism in women with migraine taking topi-
ramate, and found osteopenia in 53% of them. The risk
seemed to be associated with duration of use but not
dose.
A risk of bone loss with long-term topiramate treat-
ment is plausible because it is a carbonic anhydrase
inhibitor. The mild metabolic acidosis it produces may
have an effect on bone metabolism and turnover. This
is concerning because migraine is a condition of long
duration and most patients requiring long-term pro-
phylaxis for it are women.
Discussion
The package insert for topiramate recommends
obtaining baseline and periodic serum bicarbonate
levels in patients using topiramate, based on a correla-
tion between chronic metabolic acidosis and fatigue. It
is unclear, however, whether serum bicarbonate levels
can be used to indicate a risk for bone loss. A number
of strategies have been proposed to minimize or
prevent bone loss in patients treated with antiepileptic
drugs. At present, however, evidence is insufficient to
make strong recommendations for these proposals,
which include:
r Measurement of bone mineral density at the start
of treatment and periodically on an individualized
basis.
r Monitoring of vitamin D (25-OHD) levels so that
vitamin D supplementation can be adjusted on an
individualized basis.
r Recommendations for adequate calcium intake
and vitamin D supplementation with 400–
2000 IU/day as prophylaxis.
Many patients have questions about the long-term
safety of migraine preventive treatment. This is under-
standable because most people with migraine are oth-
erwise healthy. Migraine itself confers little long-term
health risk, unlike other conditions such as epilepsy
for which long-term preventive treatments might be
used. Thus the balance of benefits and harms of

long-term treatment with drugs such as topiramate
will be weighed differently depending upon whether
they are used for migraine or epilepsy.
Diagnosis
Chronic migraine.
Tip
Most of the troublesome side effects of topiramate
are reversible when treatment is stopped, but patients
should be cautioned about the possibility of long-term
treatment-related bone loss.
A woman worried about whether her
contraceptive will work when she is on
topiramate
Case
A 21-year-old woman with chronic migraine called
her physician to report that she had missed her last
menstrual period. She was taking an oral combina-
tion hormonal contraceptive for contraception and
menorrhagia. Six months ago she had started topi-
ramate. When she went to the pharmacy to fill the
prescription, the pharmacist told her there was an
interaction between topiramate and oral contracep-
tives that might increase her risk of becoming preg-
nant. At the time, her physician had reassured both
her and the pharmacist that this interaction was not
clinically important with typical anti-migraine doses
of topiramate. However, in view of her missed period
the patient was concerned that perhaps the pharma-
cist had been right, and that she might now be preg-
nant. Although the physician had used these two med-
ications in many patients over the years, she was also
worried.
What is the interaction between topiramate
and combination hormonal contraceptives?
Topiramate decreases serum concentrations of ethinyl
estradiol, the active estrogen component in many com-
bined hormonal contraceptives. Studies show that the
blood concentration of ethinyl estradiol is reduced by
an average of 18% in women who are also taking top-
iramate 200 mg daily. The decline in estrogen levels
Chapter 8: Pitfalls in preventive drug therapy
depends upon the dose of topiramate: estrogen levels
decreased by an average of 21% when used with a daily
dose of 400 mg of topiramate, and 30% with a dose of
800 mg/day. This interaction is substantial enough to
interfere with the contraceptive efficacy of the newer
low estrogen dose combination contraceptives that are
now in common use.
When used for migraine prophylaxis, however,
topiramate is rarely given in doses above 150 mg/day;
a more typical dose is 100 mg/day. One study showed
that healthy volunteers taking topiramate at doses of
50–200 mg/day did not experience statistically signifi-
cant decreases in ethinyl estradiol concentrations. On
the basis of these data, which are described in the
package insert, it is very unlikely that topiramate pre-
scribed at doses less than 200 mg/day will decrease
the efficacy of combination estrogen–progestin con-
traceptives. For patients who might be imperfectly
compliant with oral contraceptive regimens, however,
one might consider the use of a combination hor-
monal contraceptive with a slightly higher dose of
ethinyl estradiol. In this case, the patient had a neg-
ative pregnancy test and a normal menstrual period
two weeks later. The patient decided to continue topi-
ramate, but changed to a combination hormonal con-
traceptive with 30 ␮g of ethinyl estradiol “for peace of
mind.”
Diagnosis
Chronic migraine.
Tip
At doses less than 200 mg/day, topiramate does not
interfere with contraceptive efficacy.
An older man treated for tension-type
headache who has a seizure
Case
A 66-year-old man with history of hypertension,
hyperlipidemia, and peptic ulcer disease was referred
to the headache clinic to discuss treatment for his
migraines. Headaches had become more frequent over
the last year, and he attributed this worsening to emo-
tional stress and worry about his other health prob-
lems. His doctor had started him on amitriptyline
25 mg at bedtime, and his headache frequency had
decreased from three times a week to once a week. He
137
 Chapter 8: Pitfalls in preventive drug therapy

Table 8.8. Some headache treatments that may lower the

seizure threshold
Discussion
Certain medications are more frequently associated
Category Drug Example
with drug-induced seizures than others. In a recent
Antidepressants Tricyclic antidepressants
SSRIs and selective serotonin–
retrospective analysis, the drugs most frequently asso-
norepinephrine reuptake ciated with seizure induction were bupropion (23%),
inhibitors (SNRIs) diphenhydramine (8.3%), tricyclic antidepressants
Local anesthetics (if systemic Lidocaine (7.7%), tramadol (7.5%), amphetamines (6.9%), isoni-
absorption occurs) Bupivacaine azid (5.9%), and venlafaxine (5.9%). Since a large num-
Procaine
ber of the events analyzed in this study were described
Analgesics Fentanyl as suicide attempts, it is probably that the risk is dose
Meperidine
Pentazocine related as well as drug related. Overall, about 18% of
Propoxyphene seizure cases involved the use of more than one medi-
Tramadol cation known to lower the seizure threshold.
Neuroleptics Clozapine
Phenothiazines
Butyrophenones Diagnosis
Other Anticholinergics Probable medication-induced seizure in a patient
Anticholinesterases taking multiple medications with epileptogenic side
Antihistamines
Baclofen effects.
Hyperbaric oxygen
Lithium
Tip
also reported improved sleep. At this visit he reported The use of multiple epileptogenic medications should
continued worry about the migraines he still had, how- be avoided when possible, especially in older patients.
ever, because he had not found any effective treatment
for the infrequent but very severe events. Triptans were A fatigued patient on two blood
contraindicated because he had coronary atheroscle-
rosis, and he could not take anti-inflammatory drugs
pressure medicines
such as aspirin because of a previous problem with
gastric ulcers. His physician thus prescribed tramadol.
Case
Three weeks later the patient was admitted to the hos- A 47-year-old woman was being treated for intractable
pital for evaluation after suffering a witnessed, gener- chronic migraine. She had previously experienced a
alized tonic–clonic seizure. small reduction in headache frequency with propra-
nolol and had remained on a dose of 120 mg a day.
Multiple other trials of preventive medications had
What happened? failed to produce improvement, so verapamil was
Medications that lower the seizure threshold are added at a dose of 40 mg orally three times a day. At her
thought to cause about 6% of new-onset seizures. follow-up visit she reported profound fatigue, which
Many medications associated with an increased risk she attributed to her medications. She was having trou-
of seizures are used to treat migraine and some are ble getting out of bed and getting to work. On exami-
listed in Table 8.8. The epileptogenic effects of med- nation, her blood pressure was 95/62 mm Hg and her
ication are not often taken into consideration when pulse was 48 beats per minute.
prescribing treatment for patients with no prior his-
tory of or risk factors for seizure. In clinical prac-
tice, drug-induced seizures are rare in patients who are
What was the likely cause of her fatigue?
using a single medication that lowers seizure thresh- Nonselective beta-adrenergic blockers, including pro-
old. In contrast, the risk of inadvertent seizures is pranolol, inhibit sympathetically mediated increases
higher in patients who are prescribed a combination of in heart rate and cardiac contractility. Calcium channel
such medications. Older patients may be particularly antagonists such as verapamil reduce atrioventricular
vulnerable. nodal conduction and cause peripheral vasodilation.

138

Used together, these medications may produce a syn-
ergistic decrease in cardiac conduction, heart rate, and
contractility. This can lead to symptoms such as fatigue
that are caused by bradycardia and reduced cardiac
output. Peripheral edema also may develop as a result
of vasodilation.
Caution should be exercised when prescribing
two migraine preventive medications with overlapping
mechanisms of action. Another example of migraine
preventive medications where a deleterious overlap
in effect might be expected in combination would be
the use of beta adrenergic blockers with angiotensin-
converting enzyme inhibitors or angiotensin recep-
tor blockers (such as lisinopril or candesartan, respec-
tively). This combination would also be likely to
lower blood pressure significantly and perhaps pro-
duce fatigue or syncope.
Combinations of antiepileptics used for migraine
prevention may also produce synergistic adverse
events. Concurrent use of sodium valproate and top-
iramate, for example, may increase the risk of hyper-
ammonemia. The concurrent use of valproate and
lamotrigine may increase the risk of development of
Stevens–Johnson syndrome. In contrast, gabapentin
can often be combined with other antiepileptic drugs
without causing intolerable side effects. Its useful-
ness for migraine prevention, however, is not set-
tled. Recent guidelines for preventive migraine ther-
apy issued by the AAN and the AHS concluded that
current evidence is insufficient to recommend for or
against use of gabapentin for migraine prophylaxis.
Nonetheless, as with other drugs in that category, the
drug is still in widespread use for migraine prophylaxis
based on clinical impressions of benefit.
Discussion
The use of medications in combination has been sug-
gested in the management of refractory migraine and
in most instances is considered safe and well toler-
ated. The potential complications of such combina-
tions, though, should be borne in mind. Anticipating
drug side effects is important. Many potential syner-
gies can be suspected based on what is known about
a drug’s mechanisms of action. Since most drugs have
multiple actions, however, this is not always the case.
Table 8.9 lists combinations of preventive medications
that should be used with caution due to the potential
for overlapping side effects.
Chapter 8: Pitfalls in preventive drug therapy
Table 8.9. Combinations of preventive headache medications
that should be avoided
Combination Comment
Any combination of An exception could be made for
antihypertensives patients with treatment-resistant
hypertension
Two or more Gabapentin might be an exception to
antiepileptic drugs this rule because it is generally well
tolerated both alone and when used
with other drugs
Topiramate and A recent randomized trial
propranolol demonstrated no benefit for the
combination compared with
topiramate treatment alone
Two or more In addition to synergistic side effects of
antidepressants agitation or somnolence, there is a risk
of serotonin syndrome with this
combination. Psychiatrists occasionally
use a full dose of an SSRI or SNRI with a
small dose of a tricyclic antidepressant
at night to help with sleep
Diagnosis
Profound fatigue related to drug-induced hypotension
and bradycardia.
Tip
Avoid prescribing drugs with overlapping side effect
profiles.
How about Botox for episodic
migraine?
Case
A 42-year-old woman had a 20-year history of
migraine without aura, with headaches consistent with
migraine occurring about eight days a month for the
last three years. On the advice of a friend she began
treatment for her headaches with intramuscular injec-
tions of 155 units of onobotulinumtoxinA every three
months. After one year of therapy she had not noted
significant improvement. She presented for a second
opinion at a headache center; she suspected that the
lack of improvement was due to an inadequate dose
of botulinum toxin. She requested that the headache
center take over the treatment and requested a letter
to her health insurance company in support of con-
tinued therapy using 300 units of the drug every three
months. She was not overusing analgesic medications
and her past medical history was otherwise notable
139
 Chapter 8: Pitfalls in preventive drug therapy
only for a mild anxiety disorder. Her neurologic exam-
ination was normal and her body mass index (BMI)
was 33.
Is onabotulinumtoxinA the best therapeutic
recommendation for this patient’s pattern of
headache?
Although the use of onabotulinumtoxinA is supportd
by an FDA indication for chronic migraine, it is not
approved for treatment of episodic migraine. A large
number of randomized clinical trials have failed to
show benefit in episodic migraine and AAN treatment
guidelines currently label onabotulinumtoxinA ther-
apy as “probably ineffective” for treatment of episodic
migraine. The likely explanation for the lack of bene-
fit of this therapy in the patient described in this case
is that this is simply the wrong choice of treatment for
her condition.
It may have seemed logical to use onabotulinum-
toxinA therapy; one argument might have been that
this was a safe therapy for use in a motivated patient
with high frequency migraine who might have been
in the process of transformation to a chronic pattern.
Why not, it could be asked, just skip all the systemically
active preventive medication trials with their possible
associated side effects and jump all the way to onabo-
tulinumtoxinA treatment? There are several problems
with this approach. The first, as noted, is that there is
high quality evidence that the drug is not effective for
episodic migraine. Why this is so is not entirely clear,
but may be tied to its mechanism of action and the
processes that come into play when migraine trans-
forms from an episodic to a chronic form. In part,
the mechanism of action of onbotulinumtoxinA in
chronic migraine may relate to peripheral inhibition
of neurotransmitter and neuropeptide (e.g. substance
P, calcitonin gene-related peptide [CGRP], glutamate)
release which is related to inhibition of central sensiti-
zation. In episodic migraine patients, whose disorder
is unlikely to involve sustained central sensitization,
onabotulinumtoxinA may not work.
What therapy should be offered to
the patient?
This patient should be advised that onabotulinum-
toxinA therapy has been shown to be ineffective for
her condition. Instead, a combination of abortive and
preventive medications should be considered, per-
140
haps combined with lifestyle management including
exercise and weight control, along with attention to
any comorbid conditions such as anxiety that may be
aggravating her headaches.
Discussion
The FDA approved onabotulinumtoxinA for treatment
of chronic migraine in 2010. International Classifi-
cation of Headache Disorders (ICHD)-3 beta crite-
ria for chronic migraine require the presence of more
than 15 headache days a month, with a headache
day defined as one with headache for more than four
hours. Headaches must have features of migraine, or be
relieved by the use of a migraine-specific drug (triptans
or ergots) on at least eight days a month.
The approved treatment protocol for onabo-
tulinumtoxinA for chronic migraine is the administra-
tion of 155 units intramuscularly in 31 fixed sites. The
drug is diluted with saline, and individual injections of
5 units are made in the muscles depicted in Figure 8.1.
Subsequent analysis further suggests that patients
with concomitant medication overuse derive a simi-
lar benefit from onabotulinumtoxinA therapy to those
without, and that in many patients the clinical effect
increased over subsequent injection cycles. Reported
adverse events overall leading to study discontinuance
were low (3.8%) in the clinical trial treatment groups.
Neurotoxins appear to be taken up in peripheral
motor neurons, where they disrupt the protein com-
plex that facilitates vesicle fusion and release from
the axonal endplates. Neurotoxins also may affect sen-
sory neurons by inhibiting release of proinflamma-
tory mediators at several sites within the neuron. More
specifically, onabotulinumtoxinA could suppress neu-
rogenic inflammation near the scalp or facial injec-
tion site by preventing the release of the neuropep-
tides CGRP and substance P from free nerve endings
that provide sensory innervation to the skin and mus-
cles. In addition, neurotoxins may exert central effects
by blocking the release of CGRP and glutamate from
nociceptive nerve fibers in the spinal cord, leading to
a suppression of stimulation of second-order neurons
that are theoretically associated with the maintenance
of central sensitization and pain.
The exact mechanism of onabotulinumtoxinA in
chronic migraine is unknown, and perhaps multiple
mechanisms are involved, as above, including: inhi-
bition of neurotransmitter release from both motor
neurons and sensory nociceptive neurons, leading to

Figure 8.1 Paradigm for injection of onabotulinumtoxinA for chronic migraine.
a reduction in both peripheral and central sensitiza-
tion; direct antinociceptive effects through blockage
of CGRP and glutamate release; and lastly possibly
a direct muscle relaxant effect that may also play
a role in headache management in some patients.
The most likely mechanism of action is that the
preventive effect of onabotulinumtoxinA in chronic
migraine is due to its ability to inhibit motor neu-
ron overactivity and sensory neuron hyperexcitabil-
ity, leading to suppression of peripheral and central
sensitization.
One barrier to use of onabotulinumtoxinA is
cost, although this may be partially offset by sav-
ings through reduced usage of expensive abortive
agents such as triptans and by fewer emergency
department visits by those who respond to the treat-
ment. Preapproval from the patient’s health insurer
is often required, a process that adds work and can
significantly delay the initiation of therapy. Onabo-
tulinumtoxinA is not interchangeable with other
botulinum neurotoxins and at the time of this writ-
ing is the only FDA-approved neurotoxin for chronic
migraine.
Diagnosis
Episodic migraine without aura.
Tip
Though useful in chronic migraine, onabotulinumtox-
inA (Botox) is not indicated for and is not useful in
Chapter 8: Pitfalls in preventive drug therapy
the treatment of episodic migraine headache. Its use
should be restricted to patients with well-documented
chronic migraine.
A young woman with headache after
head trauma
Case
A 19-year-old woman presented to the headache clinic
with her mother to discuss persistent headaches after
head trauma. The initial head injury had occurred one
year ago while she was playing soccer and hit the shoul-
der of another player with her head. There was no loss
of consciousness but she immediately developed dizzi-
ness, nausea, holocephalic headache, and balance dif-
ficulties. She was taken off the field and evaluated by
her team trainer, who diagnosed her with a concus-
sion. The concussive symptoms improved over the next
three months without medication and she was able to
return to play.
Several months later, during a spring-break trip,
she sustained a second head trauma while off-roading
on an all-terrain vehicle (ATV). She was not wear-
ing a helmet and her ATV overturned, resulting in
head trauma with loss of consciousness for around a
minute. Her symptoms, including headache, imme-
diately returned and have been persistent since. The
headaches are present daily, usually better in the morn-
ing and worse in the evening. Activity, concentration,
trying to read, sustained visual focus, loud noise, and
141
 Chapter 8: Pitfalls in preventive drug therapy
bright lights all worsen the headache. The pain may
reach 8/10 and can be pulsing or throbbing, though
still holocephalic. She denies any aura. She has been
tried on amitriptyline without any benefit.
What factors predisposed this patient to the
development of post-traumatic headache?
In a recent multicenter study done to determine fac-
tors associated with headache after traumatic brain
injury (TBI), the most significant risk factor for post-
traumatic headache (PTH) was a pre-injury diag-
nosis of migraine or other headaches. Penetrating-
type TBI and female sex were also associated. In
a pediatric study, adolescents were more likely to
develop post-concussive headache than younger chil-
dren. Other factors associated with development of
chronic PTH include mild (rather than moderate or
severe) head trauma and low educational and socio-
economic status. While not formally studied as a risk
factor for headache, repeat head trauma often causes
more severe post-concussive symptoms.
Upon further questioning, the patient denied a his-
tory of headache prior to the injury. She was very prone
to motion sickness both as a child and through her
adolescent years, however, and she had a strong family
history of migraine. Both of these factors suggest an
underlying predisposition to headache. This, in com-
bination with her age, sex, and multiple head trau-
mas, may have contributed to the risk of developing
PTH.
What treatment options are available for
this patient?
There is very little high quality evidence on which
to base treatment of PTH. Prophylactic therapies for
PTH have not been compared in randomized con-
trolled trials, but open-label studies suggest benefit
from amitriptyline, topiramate, valproate, and propra-
nolol. Case reports have also described improvement
after botulinum toxin treatments. We approach PTH
as though it were the underlying headache disorder it
most resembles, treating migrainous headaches with
migraine preventatives, cluster-like headaches with
verapamil, etc. This approach extends to symptomatic
treatment, and in our experience patients who have
migrainous PTH exacerbations may respond well to
triptan therapy.
142
In this case, the patient had headaches with
migrainous features and the care plan was modeled
after treatment of migraine. She was started on topira-
mate with partial improvement, and had nearly com-
plete resolution after the addition of low-dose propra-
nolol. A trial of sumatriptan was also successful for
management of individual severe headaches.
Discussion
The incidence of TBI is increasing in many popu-
lations, particularly among soldiers returning from
combat and young athletes. Increased recognition of
TBI in athletes may also be contributing to the rise
in diagnosis. Headache is the most common symp-
tom accompanying concussion, is often the first post-
concussive symptom to develop, and is typically the
last to resolve. PTH does not have any specific clini-
cal criteria, and the diagnosis is made based on a tem-
poral relationship to head trauma. Currently, the diag-
nosis is made if the headache develops within seven
days of head or neck trauma, although many providers
who work with TBI patients describe development of
headache with a longer delay. This is a subject of some
debate in the headache community.
A headache meeting the clinical criteria for
migraine is the most commonly described phenotype,
but headaches resembling tension-type headache,
cluster headache, occipital neuralgia, and cervico-
genic headache have also been described after head
trauma. The headache may also be nonspecific, not
fully resembling any primary headache disorder. Diag-
nosis can be complicated in younger patients as the
first presentations of many primary headache disor-
ders typically occur at this age. In our experience,
mild head trauma may be a precipitating event for
the emergence of an underlying primary headache
disorder.
There are no data to suggest when to start pro-
phylactic treatment for PTH. Some providers feel that
starting treatment early, after a few weeks of headache,
may return the patient to function more quickly. This
approach may delay return to play/work, however, as
the current guidelines for returning to full activity
require that the patient is asymptomatic off medica-
tions. Other providers wait for several months of per-
sistent headache prior to starting preventive treatment.
If the patient is still having bothersome headache sev-
eral months after the injury, preventive therapy is
indicated.

As this case illustrates, patients with repeated head
trauma may experience more severe post-concussive
symptoms with each successive head trauma. Patients
should be educated about the risks of successive head
traumas and advised to wear helmets. After a second
concussion, a discussion about whether to return to
playing contact sports may be warranted.
Diagnosis
Chronic post-traumatic headache after mild head
injury.
Tip
Post-traumatic headache is more likely to occur after
mild head injuries and with repeat head injuries. Treat-
ment is aimed at the headache type it most resembles.
Further reading
When to start prevention in patients with frequent
headaches
Buchanan TM, Ramadan NM. Prophylactic
pharmacotherapy for migraine headaches. Semin Neurol.
2006;26(2):188–98.
Weight gain and migraine
Blumenfeld AM, Bloudek LM, Becker WJ, et al. Patterns of
use and reasons for discontinuation of prophylactic
medications for episodic migraine and chronic
migraine: results from the second international burden
of migraine study (IBMS-II). Headache. 2013;53(4):
644–55.
Vo M, Ainalem A, Qiu C, et al. Body mass index and adult
weight gain among reproductive age women with
migraine. Headache. 2011;51(4):559–69.
Winter AC, Wang L, Buring JE, Sesso HD, Kurth T.
Migraine, weight gain and the risk of becoming
overweight and obese: a prospective cohort study.
Cephalalgia. 2012;32(13):963–71.
Young WB, Rozen T. Preventive treatment of migraine:
effect on weight. Cephalalgia. 2005;25(1):1–11.
Principles and guidelines for migraine prevention
Loder E, Burch R, Rizzoli P. The 2012 AHS/AAN guidelines
for prevention of episodic migraine: a summary and
comparison with other recent clinical practice
guidelines. Headache. 2012;52(6):930–45.
Rizzoli, P. Acute and preventive treatment of migraine.
Continuum (Minneap Minn). 2012;18(4):764–82.
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Silberstein SD, Holland S, Feitag F, et al. Evidence-based
guideline update: pharmacologic treatment for episodic
migraine prevention in adults: report of the Quality
Standards Subcommittee of the American Academy of
Neurology and the American Headache Society.
Neurology. 2012;78:1337–45.
Refractory migraine
Peterlin BL, Calhoun AH, Siegel S, Mathew NT. Rational
combination therapy in refractory migraine. Headache.
2008;48(6):805–19.
Silberstein SD, Dodick DW, Lindblad AS, et al.
Randomized, placebo-controlled trial of propranolol
added to topiramate in chronic migraine. Neurology.
2012;78:976–84.
Combination treatment of migraine
Domingues RB, Silva AL, Domingues SA, Aquino CC,
Kuster GW. A double-blind randomized controlled trial
of low doses of propranolol, nortriptyline, and the
combination of propranolol and nortriptyline for the
preventive treatment of migraine. Arq Neuropsiquiatr.
2009;67(4):973–7.
Holroyd KA, Cottrell CK, O’Donnell FJ, et al. Effect of
preventive (beta blocker) treatment, behavioural
migraine management, or their combination on
outcomes of optimised acute treatment in frequent
migraine: randomised controlled trial. BMJ. 2010;341:
c4871.
Paresthesias on topiramate
Lee ST, Chu K, Park JE, et al. Paresthesia as a favorable
predictor of migraine prophylaxis using topiramate. Eur
J Neurol. 2007;14(6):654–8.
Luykx J, Mason M, Ferrari MD, Carpay J. Are migraineurs
at increased risk of adverse drug responses? A
meta-analytic comparison of adverse drug reactions in
epilepsy and migraine. Clin Pharmacol Ther. 2009;85(3):
283–8.
Silberstein SD. Control of topiramate-induced paresthesias
with supplemental potassium. Headache. 2002;42(1):85.
Medication overuse headache
Hagen K, Albretsen C, Vilming ST, et al. Management of
medication overuse headache: 1-year randomized
multicentre open-label trial. Cephalalgia. 2009;29(2):
221–32.
Tepper SJ. Medication-overuse headache. Continuum
(Minneap Minn). 2012;18(4):807–22.
Orthostatic hypotension
Mussi C, Ungar A, Salvioli G, et al. Orthostatic hypotension
as cause of syncope in patients older than 65 years
143
 Chapter 8: Pitfalls in preventive drug therapy
admitted to emergency departments for transient loss of
consciousness. J Gerontol A Biol Sci Med Sci.
2009;64(7):801–6.
O’Mahony D, Foote C. Prospective evaluation of
unexplained syncope, dizziness, and falls among
community-dwelling elderly adults. J Gerontol A Biol Sci
Med Sci. 1998;53(6):M435–40.
Angle-closure glaucoma from amitriptyline
Boentert M, Aretz H, Ludemann P. Acute myopia and
angle-closure glaucoma induced by topiramate.
Neurology. 2003;61:1306.
Bouassida W. Drug-induced acute angle closure glaucoma.
Curr Opin Ophthalmol. 2007;18:129–33
Long-term side effects of topiramate
Ali II, Herial NA, Orris M, Horrigan T, Tietjen GE.
Migraine prophylaxis with topiramate and bone health
in women. Headache. 2011;51:613–16.
Láinez MJ, Freitag FG, Pfeil J, et al. Time course of adverse
events most commonly associated with topiramate for
migraine prevention. Eur J Neurol. 2007;14(8):900–6.
Mikati MA, Ataya N, El-Hajj Fuleihan G. Re: Epilepsy-
associated bone mineral density loss should be
prevented. Neurology. 2009;72(10):943; author reply
943–4.
Pack AM, Morrell MJ. Adverse effects of antiepileptic drugs
on bone structure: epidemiology, mechanisms and
therapeutic implications. CNS Drugs. 2001;15(8):
633–42.
Topiramate and oral contraceptive efficacy
Reddy DS. Clinical pharmacokinetic interactions between
antiepileptic drugs and hormonal contraceptives. Expert
Rev Clin Pharmacol. 2010;3(2):183–92.
Drug-induced seizures
Ruffmann C, Bogliun G, Beghi E. Epileptogenic drugs: a
systematic review. Expert Rev Neurother. 2006;6(4):
575–89.
144
Synergistic side effects and drug-induced headache
Brouwers L, Iskar M, Zeller G, van Noort V, Bork P.
Network neighbors of drug targets contribute to
drug side-effect similarity. PLoS One. 2011;6(7):
e22187.
Chakor RT, Bharote HS. Topiramate-valproate-induced
encephalopathy in migraine. Headache. 2012;52(8):
1321–2.
Chen HC, Tsai SJ. Trazodone-induced severe headache.
Psychiatry Clin Neurosci. 2011;65(7):681–2.
Garcia-Serna R, Mestres J. Anticipating drug side effects by
comparative pharmacology. J Expert Opin Drug Metab
Toxicol. 2010;6(10):1253–63.
OnabotulinumtoxinA for chronic migraine
Blumenfeld A, Evans RW. OnabotulinumtoxinA for
chronic migraine. Headache. 2012;52:142–8.
Blumenfeld A, Silberstein SD, Dodick DW, et al. Method of
injection of onabotulinumtoxinA for chronic migraine: a
safe, well-tolerated, and effective treatment paradigm
based on the PREEMPT clinical program. Headache.
2010;50:1406–18.
Durham PL, Cady R. Insights into the mechanism of
onabotulinumtoxinA in chronic migraine. Headache.
2011;51:1573–7.
Evans RW. A rational approach to the management of
chronic migraine. Headache. 2013;53:168–76.
Post-traumatic headaches
Erickson JC, Neely ET, Theeler BJ. Posttraumatic headache.
Continuum (Minneap Minn). 2010;16(6 Traumatic Brain
Injury):55–78.
Lucas S. Headache management in concussion and mild
traumatic brain injury. PM R. 2011;3(10 Suppl 2):
S406–12.
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headache severity (density and functional impact) after
traumatic brain injury: a longitudinal multicenter study.
Cephalalgia. 2013;33(12):998–1008.
 Chapter
Pitfalls in nonpharmacologic treatment
9 of headache
Although medications are the mainstay of headache
treatment, nonpharmacologic treatments are often
pursued as alternatives by both patients and practi-
tioners. “Nonpharmacologic treatment” is a term often
used to refer to a heterogeneous group of therapies.
These range from adjunctive integrative therapies such
as vitamins, supplements, mind–body practices, and
behavioral therapies to potentially invasive procedures
including surgery or nerve blocks.
Interest in nonpharmacologic treatments of all
kinds is increasing in both popular culture and among
providers. As more evidence about these treatments
emerges they are becoming more mainstream and
patients feel more comfortable asking for or about
them. Many of these treatments have useful roles
in headache management. They can be helpful for
patients who do not tolerate medications or are averse
to the idea of taking medications, and can also be
useful adjuncts for those already using pharmacologic
therapy.
While these therapies may seem benign, they
are not without risk. In fact, the risks of the non-
medication treatments are often overlooked because
these treatments are perceived as safer and less likely
to cause adverse events than traditional medical ther-
apy. In many cases, however, there is a lack of good
data about safety, and nonpharmacologic medications
that are classified as dietary supplements are exempted
from strong regulatory oversight by the US Food and
Drug Administration (FDA). These things should lead
to considerable caution on the part of doctors in rec-
ommending some of these interventions to patients.
Most of all, nonpharmacologic interventions should
not be assumed to be risk free, but instead should be
evaluated in a similar fashion to any other interven-
tion. In general, however, these treatments are well
tolerated.
In this chapter, we will discuss the indications and
pitfalls of some commonly used nonpharmacologic
treatments for headache. Surgical interventions some-
times considered for migraine treatment are also dis-
cussed here. We will start, however, by considering the
role of trigger avoidance in headache management –
perhaps the most basic nonpharmacologic interven-
tion of all.
A young woman with dietary triggers
for headache
Case
A 23-year-old woman presented for a second opinion
regarding her headaches. She had had headaches that
met criteria for migraine without aura about twice a
week since she was a young teenager. Initially these
were well managed with nonprescription analgesics
such as acetaminophen or ibuprofen, but over the last
several years these had stopped working. A previous
physician had started her on a triptan but also told her
that her headaches were likely due to environmental
factors, specifically her diet. Since that visit about one
year ago, she had eliminated multiple foods, includ-
ing lactose, gluten, soy, tree nuts, alcohol, and choco-
late. Although none of these changes had substantially
reduced the frequency of her headaches, the patient
was afraid to reintroduce any of these foods lest her
headaches worsen. She was very distressed in the office
and stated that she is losing weight because she did not
know what she could eat, and that her dietary restric-
tions prevented her from going out with her friends.
On exam she was very thin but the neurologic exam
was normal.
What is the relationship between dietary
factors and migraine?
The possible effect of specific foods or even entire diets
on frequency of migraine is a topic of much interest to
145
 Chapter 9: Pitfalls in nonpharmacologic treatment
both headache practitioners and patients. Up to 46%
of migraine patients identified dietary triggers in one
study, and another found that 75% of patients with
chronic headache reported they were aware of possi-
ble connections between food intake and headache.
There are several possible mechanisms by which
a certain food could be associated with migraine:
direct toxic or metabolic effect, vasodilation, and aller-
gic response are all plausible biologic explanations,
while conditioned taste aversion, expectation and self-
fulfilling prophecy, or confounding factors (such as
when stress triggers both consumption of a certain
food and headache, thus causing the appearance of the
food triggering the headache) are behavioral explana-
tions. The role of anchoring cannot be overstated, as
patients will almost always have eaten something in the
24 hours prior to having a migraine, thus making diet
an easy target when searching for a cause.
Fasting is a well-established trigger for migraines.
This is often seen in patients who fast for religious
reasons, including the observance of Yom Kippur or
Ramadan. Patients who habitually skip meals may find
that eating more regular meals may help to reduce
headache frequency.
In this case, it seems unlikely that any individual
dietary trigger is responsible for her headaches. This
case illustrates the potential harm in placing undue
emphasis on dietary triggers in migraine.
What is the quality of evidence about
dietary triggers for migraine and what is the
best advice for this patient?
Given the subjective experience of patients and the
emphasis given to dietary triggers in popular literature,
controlled studies are surprisingly inconclusive and
by and large do not support any universal statements
about the relationship between diet and migraine.
Alcohol, chocolate, and cheese are the dietary trig-
gers most commonly reported by migraineurs. In
one placebo-controlled dietary challenge study, sub-
jects who identified chocolate as the dietary trig-
ger were fed bars containing chocolate or a closely
matched placebo, and headaches in fact were more
likely to occur in the group fed chocolate. No study
has found that cheese or its hypothesized triggering
agent, tyramine, reliably causes migraine. Red wine,
however, does have some evidence to support activ-
ity as a migraine trigger. In a study comparing red
146
wine with disguised vodka, 9 of 11 patients who drank
red wine developed a headache while none of the 8
who drank vodka did. As limited as these studies may
seem, there is even less evidence for any influence of
gluten or lactose. No studies examining the effect of
a gluten- or lactose-free diet on headache have been
performed.
In this case, the patient could be counseled about
the lack of clear evidence for a relationship between
diet and migraine. It may be helpful, however, to
provide anecdotal support for the idea that certain
foods seem to reliably trigger headaches in some
patients. She need not be hostage to her diet, however.
She could try gradually reintroducing foods one at a
time, keeping a headache diary to assess the effect on
headaches.
Discussion
There is clearly tremendous interest in dietary precip-
itants of headache and migraine, both among patients
and among physicians. A “migraine diet” of some kind
is a common component of many popular lay pro-
grams for treatment of migraine. The rise of public
awareness about food intolerance and allergies, along
with widespread acceptance of elimination diets also
contributes to interest in this approach to management
of medical conditions. A possible dietary effect on
migraine is biologically plausible, especially for sub-
stances that have direct or indirect effects on vascu-
lar tone or levels of biogenic amines that might be
involved in migraine. The evidence, however, is scant,
making an evidence-based recommendation about
dietary triggers in migraine challenging.
It should also be noted that recommending the
elimination of multiple food groups from the diet
is not entirely benign. A lack of specific nutrients
may result, or, as in this patient, an overall lack of
adequate caloric intake. Because the list of potential
dietary migraine triggers is vast, large food groups
become suspect to the patient. Over time this can
encourage secondary anxiety around dietary choices,
which in and of itself may contribute to worsened
headache. Placing undue emphasis on dietary trig-
gers of migraine may also have the unintended effect
of making patients feel that they are entirely respon-
sible for the frequency of their headaches. The bal-
ance between supporting a healthy lifestyle by avoid-
ing known triggers and placing too much emphasis on
environmental factors is a fine one.

If a patient expresses interest in an elimination diet,
it may be helpful to give a systematic framework within
which to conduct such trials. They may be encour-
aged to keep a diary for a time, identify a list of pos-
sible triggering foods, and then track headache fre-
quency with the diary while eliminating each food
for several weeks at a time. If no improvement in
headaches is seen, the food can be reintroduced. This
approach may help to identify triggers while prevent-
ing cumulative loss of whole food groups from the
diet.
Diagnosis
Episodic migraine without aura with possible dietary
triggers.
Tip
Evidence is lacking to support a clear role for many
foods commonly assumed to be triggers of migraine.
Physicians should be cautious about recommending
highly restrictive dietary regimens for migraine, and
avoid placing undue emphasis on dietary triggers.
A young woman with frequent
headaches attempting pregnancy
Case
A 29-year-old woman presented for evaluation of
migraine headaches since age 19, which had occurred
about once a month until six months ago when they
increased in frequency. The migraines seemed to be
provoked by stress, let down from stress, lack of
sleep, skipping meals, and caffeine. She worked as
a medical assistant and had started school to train
as a physician assistant around the time that the
headaches worsened. Her quality and duration of
sleep had declined. At the time of evaluation the
headaches were occurring about twice a week, and
she had started to miss work occasionally because of
them.
She had been treating her headaches only with
acetaminophen because she was planning to attempt
pregnancy in the next several months. Her exam was
normal and she had a negative MRI and blood work
ordered by her primary care physician.
Chapter 9: Pitfalls in nonpharmacologic treatment
Is this patient’s description of headache
triggers likely to be accurate?
Most patients with migraine (between 75% and 95%)
report having headache triggers, or precipitants that
bring on a headache. The research on triggers is, how-
ever, surprisingly thin. Researching triggers is diffi-
cult as it is very difficult to isolate single triggers in
real life. Studies attempting to verify specific triggers
such as changes in barometric pressure have been
negative. Further complicating the question of trig-
gers is the phenomenon of “anchoring,” which occurs
when patients (or doctors!) connect an outcome with a
recent event. Those two conditions become connected
in the patient’s mind and evidence to support this con-
nection is unconsciously sought. Therefore, someone
may have a headache after eating tomatoes and from
then on pay more attention to headaches that occur
after eating tomatoes.
Despite the lack of evidence, however, some events
are clearly linked to the development of headaches in
some patients. In this case, the patient noted a clear
correlation between drinking coffee and developing a
headache within the next hour. When a trigger is reli-
ably reproducible, as in this example, the trigger is
likely to be accurate.
Is there a role for trigger avoidance in
this case?
Just as there is poor evidence for individual triggers for
headache, there are also very few data about the role
of trigger avoidance in the management of headache.
Despite this lack of evidence, however, we have seen
repeatedly in our clinic that patients often improve
when some effort at trigger management is under-
taken. Some triggers can be addressed with behavioral
changes, such as sleep hygiene (see Table 9.1), eat-
ing regular meals, and avoidance of situations likely to
involve strong sensory input (the perfume counter at a
department store, for example). Some triggers, how-
ever, cannot be avoided, particularly including hor-
monal variation. For some patients, avoidance of some
life stress is simply not feasible. Trigger management
alone is therefore unlikely to be an adequate preventa-
tive strategy in cases of severe or frequent headache,
but in less frequent or milder headache disorders it
may be sufficient. In a setting where preventive med-
ication therapy is not desired, these and other behav-
ioral interventions are at least a good place to start. In
147
 Chapter 9: Pitfalls in nonpharmacologic treatment
Table 9.1. Sleep hygiene principles
Maintain a regular sleep schedule, including a regular bedtime
and waking time
Do not sleep more than is necessary to feel rested. Do not stay
in bed long after waking up
Do not “force” sleep. If unable to sleep after 20 minutes, get out
of bed and do something calming
Avoid caffeine after 2 p.m. and alcohol in the evenings
Avoid smoking, especially at night
Do not go to sleep on an empty stomach or just after eating
Keep a daily exercise schedule, but avoid exercise within 4 hours
of bedtime
Let go of worries before bed. It may help to take a warm bath
before bed
Avoid electronics including TV before bed or in the bedroom
this case, quality and duration of sleep was addressed
with sleep hygiene and her headaches decreased in fre-
quency to about once a week. These were relatively well
managed with acetaminophen.
Discussion
We distinguish between migraine triggers, which
increase the probability of a migraine attack in the
short term (usually ⬍ 48 hours) and migraine aggra-
vating factors, which are associated with a longer-term
(usually weeks to months) increase in the severity or
frequency of attacks. The most commonly reported
triggers, in addition to stress/tension, are menstru-
ation in women, sensory input (bright lights, loud
sounds, strong odors), lack of sleep, and skipping
meals. It also seems likely that triggers may be additive,
in that one trigger alone may not be sufficient to cause
headache but multiple simultaneous triggers (such as
exposure to a strong odor while sleep deprived) may
provoke a headache.
The idea that avoidance of triggers is an effective
method of migraine prevention is an old one, and we
see many patients who have been told that if they
could only identify and eliminate their headache trig-
gers, their headaches would resolve. This idea seems
to follow good old-fashioned common sense: if some-
thing gives you a headache, do not do it. There are cur-
rently no data to suggest that this is an effective strat-
egy for migraine prevention, however. Placing undue
emphasis on trigger avoidance may even be detrimen-
tal to the patient’s care. It has been suggested that try-
ing to manage migraines through trigger avoidance
can lead to a restriction of activities and increased
148
life stress. This increased stress could paradoxically
increase headaches, as the most commonly reported
headache trigger is typically “stress/tension.”
Diagnosis
Episodic migraine.
Tip
Patient recall of triggers is not always reliable. Trigger
management alone is often not sufficient treatment for
frequent or severe headache disorders.
A woman with frequent headaches and
multiple allergies
Case
A 39-year-old woman presented for evaluation of
headaches occurring about three times a week. The
headaches often met criteria for tension-type headache
but several times a month she would have more
severe migrainous headaches. The headaches had been
increasing in frequency over the last year, which she
associates with increased stress related to her mother-
in-law becoming ill and moving into their home for an
increased level of care. She also had two young chil-
dren. She reported a large number of medication aller-
gies and sensitivities including several previously tried
headache preventatives. At the visit, she stated that she
didn’t want to pursue further preventive trials because
“I do very badly with medications and they don’t work
for me anyway.”
What nonpharmacologic options are
available to this patient?
The term “nonpharmacologic” may refer to several
types of therapeutic interventions, including behav-
ioral strategies, complementary modalities, and herbs
and supplements. These last are discussed later in
this chapter. Of the treatments that do not involve
ingesting a substance of some kind, behavioral treat-
ments, which include biofeedback, cognitive behav-
ioral therapy, and relaxation training have been the
most studied. Complementary treatments (also called
complementary and alternative, alternative, or integra-
tive therapies) include acupuncture, chiropractic care,
craniosacral therapy, and massage. Table 9.2 lists some
nonpharmacologic interventions.

Table 9.2. Nonpharmacolgic therapies
Behavioral:
– Relaxation training
– Biofeedback
– Cognitive behavioral therapy
Complementary and alternative:
– Craniosacral therapy
– Acupuncture
– Chiropractic care
– Massage
The primary limitation for access for many patients
is cost, as these therapies are rarely covered by insur-
ance. Despite the greater volume of data for behav-
ioral therapies, there are typically fewer practitioners
trained in modalities such as biofeedback or relaxation
training than there are practitioners of acupuncture,
chiropractic care, or massage. Access to these behav-
ioral treatments may also therefore be limited by access
to providers. The effort required to learn a behavioral
treatment may also be a barrier to use.
For this patient, who is motivated and willing to
pay for treatments not covered by her insurance, non-
pharmacologic therapies could be recommended on
the basis of efficacy.
How successful are these interventions likely
to be?
Behavioral treatments used for treatment of migraine
are the most studied nonpharmacologic treatments. A
comprehensive review of meta-analyses and evidence-
based reviews included studies of all three types of
behavioral treatments. This review found that all three
forms of behavioral therapy are associated with a 30–
60% reduction in headache activity. Likewise, the US
Headache Consortium in 2000 gave a Grade A recom-
mendation to relaxation training, thermal biofeedback
combined with relaxation training, electromyography
(EMG) biofeedback, and cognitive behavioral therapy,
indicating that all of them “may be considered as treat-
ment options for prevention of migraine.”
Acupuncture has also been shown to be effective
for prevention of migraine. A 2009 Cochrane review
found that compared with no preventative treatment
or routine care, acupuncture reduced headache fre-
quency, overall headache days, and headache scores
at three to four months. In the one trial with long-
term follow-up, this effect seemed to dissipate by
nine months after cessation of treatment. There was
Chapter 9: Pitfalls in nonpharmacologic treatment
no difference in improvement seen when comparing
groups who received true vs. sham acupuncture. Com-
pared with pharmacologic treatments, acupuncture
had slightly better outcomes and fewer side effects.
There are very little data available regarding the effi-
cacy of craniosacral therapy.
Systematic reviews show spinal manipulation pro-
duces some improvement of migraine headache com-
pared with drug treatment, but the level of evidence
was rated as modest. There have been only a hand-
ful of very small studies of the efficacy of massage for
headache, though these did show some benefit.
While it is difficult to say which treatment will
be the most successful in a given individual, thermal
biofeedback combined with relaxation training and/or
cognitive behavioral therapy may be the most helpful
interventions.
Discussion
Behavioral treatments for management of headache
have been in use for at least 40 years. The three types
most often used and studied are cognitive behavioral
therapy, relaxation training, and biofeedback. Cog-
nitive behavioral therapy is conducted by a licensed
therapist and is short term, goal directed, and predi-
cated on the idea that changing dysfunctional thoughts
can change emotions and on reducing behaviors or
environmental events that reinforce negative thoughts.
As applied to headache, it is often used as a tool for
identifying and managing sources of stress. Empha-
sis is placed on empowering an individual to choose
their thoughts and behaviors (internal locus of con-
trol). A therapist with the goal of inducing global
relaxation or the “relaxation response” does relax-
ation training. This may be done as a guided exer-
cise or may be enhanced by biofeedback. Biofeedback
allows the patient to control physiologic parameters
through awareness of those parameters. Parameters
used include muscle tone (measured by EMG), tem-
perature, and heart rate. This may also help patients to
learn how to relax certain muscles, lower their heart
rate, or induce relaxation.
The rationale for various complementary and alter-
native therapies varies. It is sometimes difficult to
generalize about them as there is a lot of hetero-
geneity within specific modalities. Acupuncture was
developed in ancient China and involves placing nee-
dles into the skin at certain prespecified points. It is
one of the most commonly used complementary and
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 Chapter 9: Pitfalls in nonpharmacologic treatment
Table 9.3. Who will benefit from behavioral treatments?
Patients who
– Have poor or inadequate response to treatment with
medication
– Have contraindications to pharmacologic treatments for
medical reasons
– Do not tolerate pharmacologic treatments well
– Express a preference for nonpharmacologic treatments
– Are prone to overusing acute medications or have medication
overuse headache
– Have a high burden of stress or would benefit from improved
stress coping strategies
– Are pregnant or planning to become pregnant
alternative treatments, and is frequently used for treat-
ment of headache. Of the roughly 4% of the US popu-
lation who reported ever being treated with acupunc-
ture, 10% of them had been treated for headache.
Craniosacral therapy is a gentle hands-on modality
that purports to make changes to pulsations of the
intracranial fluid by manipulation of the cranium and
sacrum.
Chiropractic care and massage are usually focused
on addressing musculoskeletal abnormalities which
are hypothesized to cause headache. Although the
literature has not formally addressed this issue, we
have anecdotally seen many patients whose headaches
worsen after these treatments. Massage or manipu-
lation of the cervical area particularly may provoke
headache. Other patients, particularly those whose
headaches seem strongly related to cervical and shoul-
der tension, may derive some benefit from massage.
Evidence about the relationship between vertebral
artery dissection (VAD) and chiropractic cervical
manipulation is contradictory, but at this time we
advise our patients to avoid high velocity rotational
manipulation of the neck.
Not all patients are equally likely to benefit from
a nonpharmacologic intervention. A review of behav-
ioral therapies found that between 40% and 70%
of patients did not respond to these therapies, and
that medication overuse headache, chronic daily or
unremitting headache, and cluster or post-traumatic
headaches are all more likely to be refractory to these
treatments. The US Headache Consortium defined a
group of patients who are likely to benefit from non-
pharmacologic therapies, as shown in Table 9.3.
The patient in this case met several of the US
Headache Consortium criteria for patients who would
benefit from behavioral therapies. She was recom-
mended to undergo training for biofeedback, which
she was able to do. She was also referred for cognitive
150
behavioral therapy. With this, her headaches improved
to about once a week. Although she would have pre-
ferred to have fewer headaches, she felt this headache
frequency was manageable.
Diagnosis
Mixed tension-type and migraine headaches.
Tip
In patients who cannot or do not want to use pharma-
cologic treatment, nonpharmacologic treatments may
be helpful preventive strategies.
A woman interested in natural
treatments for migraine
Case
A 33-year-old woman presented to the office with a
history of migraines with aura since age 16. They had
occurred about twice a month until earlier in the year,
when frequency gradually increased. She was not able
to identify any precipitating factors. At the time of the
visit she was having headaches at least once and some-
times twice a week. The headaches were unchanged in
character from her previous migraines. Her neurologic
examation was normal and no further workup was felt
necessary. Preventive medications were offered, but
she said “I don’t want to go on a medication every day.
Isn’t there something natural I can take?”
What vitamins or supplements might be
recommended?
The three most commonly studied vitamins or supple-
ments for the prevention of migraine are magnesium,
vitamin B2 (riboflavin), and coenzyme Q10 (CoQ10).
Several placebo-controlled trials have examined the
efficacy of magnesium with conflicting but largely pos-
itive results. The doses tested were 360 to 600 mg/day.
Magnesium is generally well tolerated, with gastro-
intestinal symptoms being the most common and diar-
rhea being the most frequently described limiting fac-
tor. This may depend to some extent on the magnesium
salt used. Magnesium should not be used in patients
with renal failure.
Riboflavin has also been tested in controlled trials
and generally has very few side effects other than turn-
ing urine bright yellow. Riboflavin, like magnesium,

Table 9.4. Vitamins, supplements, and herbs used in the prevention of migraine
Vitamins and
supplements Doses Side effects
Magnesium 400–600 mg/day Gastrointestinal upset, diarrhea
Vitamin B2 400 mg/day Turns urine fluorescent yellow
(riboflavin)
Coenzyme Q10 150 mg/day Insomnia if taken at night
Herbs
Feverfew 150 mg daily Mouth ulcerations, gastrointestinal upset
Butterbur 75 mg bid Burping
(Petasites)
likely needs to be taken for several months for bene-
fit to be seen. CoQ10 has little data to support its use
in the adult population of migraineurs, although there
is some evidence in the pediatric literature. It seems
well tolerated aside from causing possible insomnia if
taken at night.
Magnesium and riboflavin may be good options to
recommend to the patient described in the vignette.
Magnesium may be particularly effective in patients
with aura, yet another reason to recommend it to this
patient.
Would herbal treatments be helpful?
Feverfew and butterbur (genus Petasites) are two
herbs that have been studied for migraine prevention.
In the recent American Headache Society/American
Academy of Neurology (AHS/AAN) guidelines, but-
terbur received a Category A rating, suggesting that
it “should be offered” to patients. Feverfew received
a Category B rating (“should be considered”) in the
AHS/AAN guidelines. The dose of butterbur is typ-
ically 75 mg given orally twice daily and feverfew is
typically dosed at 150 mg orally daily. There are safety
concerns about the possible presence of alkaloids in
butterbur and neither of these herbs should be consid-
ered safe during pregnancy. This may limit recommen-
dations for their use in this woman of childbearing age.
Both of these treatments are generally well tol-
erated. One sometimes bothersome effect of butter-
bur is eructation (burping). Feverfew can cause mouth
soreness and ulcerations, stomach upset, and abdom-
inal pain. Because of their benign tolerability profile,
patients often seek these herbal treatments. Lastly, for
treatment of nausea in this patient, ginger tea or ginger
supplements might be recommended.
Chapter 9: Pitfalls in nonpharmacologic treatment
Notes
Oxide and chelates may be better tolerated. May
require several months for efficacy. Useful for
migraine with aura and in pregnancy
Not studied in pregnancy. May require up to 3
months for efficacy
Less evidence for efficacy; expensive
Not safe in pregnancy
Not safe in pregnancy. Quality control of preparation
essential given toxicity of whole plant extracts
Discussion
Vitamins, supplements, and herbal treatments com-
monly used for migraine are summarized in Table 9.4.
These treatments may be useful for patients who would
like to avoid “medications” on a daily basis. Because
the FDA has limited regulatory oversight of herbal
treatments and supplements, there can be a great
deal of variation in the strength of the active ingre-
dients. The amount of active ingredient in feverfew
preparations, for example, has been shown to vary by
400% among different formulations. Different magne-
sium salts may also have differing effects, as some are
absorbed more completely than others. For this rea-
son, it can be difficult to know exactly what substances
a patient is taking when they purchase and use one of
these treatments.
Many of the trials of magnesium for prevention
of migraine have shown some benefit on migraine,
with one negative trial and one equivocal trial. Cer-
tain magnesium salts are not well absorbed and may
not be effective, though no study has compared effi-
cacy between the different magnesium salts. In our
practice, we typically recommend 400–500 mg daily
and caution that it may take several months for effects
to be seen. We find magnesium chelate and oxide to
be generally well tolerated. The clearest indication for
magnesium is probably in patients who have migraine
with aura, or in patients in whom aura is the predom-
inant symptom. Magnesium is also considered a good
choice during pregnancy. Patients who have low serum
or red blood cell magnesium may also be particularly
responsive.
Riboflavin (vitamin B2) and CoQ10 are mitochon-
drial cofactors. CoQ10 has been somewhat better stud-
ied in the pediatric literature. One trial compared
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 Chapter 9: Pitfalls in nonpharmacologic treatment
a combination of riboflavin, magnesium, and fever-
few (marketed as Migralief) with riboflavin alone and
with placebo. Both the riboflavin and the combination
group saw improvement in migraine days and other
endpoints. In our clinic, we often recommend mag-
nesium and riboflavin 400 mg daily given together.
Riboflavin has not been studied in pregnancy and
we do not recommend its use in pregnancy. Because
CoQ10 is a costly supplement with limited evidence
of benefit, we do not recommend it to patients in our
clinic. Adverse events are, however, low and there have
been no reported safety concerns, so we do not dis-
courage its use if patients are interested.
Although herbal treatments are available without
a prescription, there are safety concerns. In addition
to being associated with significant fetal risk, Peta-
sites requires another safety caveat: the rhizomes and
stalks of the plant contain hepatotoxic and carcino-
genic pyrrolizidine alkaloids. Concentrations of these
alkaloids are lowest in the leaves. Because of this, Pet-
asites should be obtained from a reputable manufac-
turer who can guarantee lack of toxicity. Feverfew has
not been studied in pregnancy and should be avoided
given its herbal medicine use to induce labor and pro-
mote uterine contractions.
Diagnosis
Episodic migraine with aura.
Tip
Although available without a prescription, the long-
term safety of herbal treatments and supraphysiologic
doses of vitamins has not been well studied. They may
be helpful for patients who are averse to taking pre-
scription medications, however.
A middle-aged man with pain in
the neck
Case
A 38-year-old data entry technician was seen with
complaints of refractory neck and head pain. He
reported that his pain began about three years ago
when his work station was equipped with a new mon-
itor and computer system. The placement of the mon-
itor required him to turn his head to the left to see it,
while the data he entered into the computer were on
cards and pieces of paper that were placed to his right.
152
The patient noted that his pain was left-sided and radi-
ated to the back and front of his head on the left. It was
constant, not throbbing, and rated on average 4–5 on
a 0–10 pain scale. He had no other associated symp-
toms such as nausea, photo or phonophobia. Initially
the pain was intermittent and cleared after the patient
left work and was able to change his posture and relax.
For the last few months, however, it had increased in
frequency and was often present after he left work. He
was using over-the-counter ibuprofen with some relief.
The patient’s physical and neurologic examinations
were normal with the exception of decreased neck
mobility, tenderness, and tightness and increased tone
of the left neck and shoulder muscles. Neck X-rays
showed minimal degenerative changes of the spine.
He was diagnosed with migraine and given rizatriptan
to use when the pain was severe. He returned several
weeks later to say that the rizatriptan was not helpful
and his pain was unchanged.
Was a diagnosis of migraine warranted?
This patient did have unilateral head pain of moder-
ate intensity, but he had no other migrainous symp-
toms. Furthermore, his pain did not respond to a rea-
sonable dose of a specific anti-migraine drug. Based on
this patient’s history, his pain was most likely originat-
ing in structures in the neck. His problem appeared
shortly after the installation of a new computer sys-
tem at work that required him to sustain a nonphys-
iologic head posture frequently and for long periods
of time. A cervical origin for his pain was suggested
by examination findings of reduced neck mobility and
increased muscle tenderness and tone in the area of
the affected muscles. His X-ray findings showed only
minimal arthritic changes that were unlikely to be the
cause of his pain.
The existence of “cervicogenic headache” is contro-
versial, and there is disagreement about how a cervi-
cal cause of headache should be diagnosed, with sev-
eral sets of diagnostic criteria in use. Most experts sug-
gest that a diagnosis of cervicogenic headache can be
made when pain is plausibly related to a neck source
and experienced in the head or neck. This requires
demonstration by imaging or other methods such as
clinical examination of a disorder in the spine or adja-
cent soft tissues that is known to be a cause of head
pain. The connection between this lesion and the pain
should be demonstrated by pain relief with diagnostic
blockade of the nerve supply of the suspected causative

structure, as well as clinical signs that implicate the
neck as a pain source.
There are plausible biologic explanations for the
radiation of pain from neck structures into the
head. The upper three cervical spinal nerves synapse
with second-order neurons in the trigeminocervical
nucleus of the upper spinal cord, which also receives
input from first-order trigeminal neurons. “Cross-
talk” between these converging neurons in the trig-
eminocervical complex may result in neck problems
producing head pain, and vice versa.
What treatment should be suggested for
this patient?
The authors of a recent systematic review of man-
ual therapies for cervicogenic headache located only
seven studies. These studies tested a variety of manual
techniques for patients with head pain originating in
the neck, including physical therapy, spinal manipula-
tion, and jaw mobilization techniques. Unfortunately,
the quality of included studies was low, with only one
including a “no treatment” control group. The authors
concluded that although there was a suggestion that
physical therapy and manipulative therapy might be
helpful for cervicogenic headache, further research
was needed to substantiate any benefits. A recent ran-
domized controlled trial of exercise and manipulative
therapy for cervicogenic headache showed benefits for
both of the individual treatments compared with a
control group. The combination of the two treatments,
however, was not clearly superior to either treatment
alone.
In the absence of consensus about the best method
of treatment, our practice is to begin with symp-
tomatic treatment such as muscle relaxants and refer
patients for physical therapy. We encourage the use
of time-limited active physical therapy interventions
such as postural training and exercises to improve
cervical muscle mobility and strength. Passive tech-
niques such as massage or ultrasound may offer tem-
porary pain relief to some patients, but they can foster
the development of dependence on continued physi-
cal therapy that is not in the patient’s best long-term
interests.
In this case, the occupational environment was
likely contributing to the patient’s problem. The phys-
ical therapist visited the patient’s workplace and
suggested rearrangement of his work station and alter-
ation of the flow and processes of his work. At a follow-
Chapter 9: Pitfalls in nonpharmacologic treatment
up visit the patient was no longer bothered by substan-
tial neck pain. Some physicians would refer patients
like this who do not respond to conservative measures
for local anesthetic blocks of the C2 nerve root, but in
our experience this invasive procedure is rarely neces-
sary. We do, however, sometimes use greater occipital
nerve blockade in these patients.
Discussion
Cervicogenic headache is a cause of unilateral head
and neck pain, usually without any side shift. The pain
is moderate to severe but otherwise lacks typical asso-
ciated features of other unilateral headache disorders.
Specifically, it is not associated with nausea, vomiting,
or photo or phonophobia, which can help distinguish
it from migraine. It is not associated with autonomic
features, which can help distinguish it from cluster
headache. It is usually provoked by neck movement
or posture. A plausible cervical source of pain, lack of
response to triptan therapy, and the absence of typical
migraine symptoms all point to a diagnosis of cervico-
genic headache.
Although cervicogenic headache is a controversial
diagnosis with no clear agreement on its features, it
likely originates from anatomic structures in the cer-
vical spine. Depending upon the criteria used to diag-
nose cervicogenic headache, its prevalence in the gen-
eral population ranges from 1% to 4.6%.
Diagnosis
Cervicogenic headache.
Tip
Nonpharmacologic approaches such as physical ther-
apy, postural training, and attention to environmental
triggers are first-line treatment measures for cervico-
genic headache.
A man with frequent headaches
interested in chiropractic treatment
Case
A 52-year-old man came to the office for evaluation
of headaches which had been gradually worsening
over the last four years. They were bilateral, poste-
rior, aching or throbbing, moderate in severity, with-
out associated features, and lasting up to several hours
153
 Chapter 9: Pitfalls in nonpharmacologic treatment
at a time. He thought they seemed worst when he
woke up in the morning, and he had attributed this
to sleeping in a bad position and thus straining his
neck. He had tried several different pillows without any
improvement. Imaging showed mild arthritic changes
in the cervical spine. He was given a diagnosis of cer-
vicogenic vs. tension-type headache and was offered
medication, but he wanted to try nonpharmacologic
treatments instead. He particularly wanted to know
if chiropractic care would be an option as one of his
friends had good success with chiropractic treatments
for back pain.
Is spinal manipulation likely to help
his headaches?
A recent systematic review of spinal manipulation for
treatment of migraine included three randomized con-
trolled trials, all of which had significant method-
ologic limitations. The study with the best methodol-
ogy showed no benefit for spinal manipulative ther-
apy, while one study showed benefit but was of poorer
quality. An attempt to develop evidence-based guide-
lines performed by a group of chiropractors and not
limited to randomized controlled trials found mod-
erate or below level evidence. They concluded that
spinal manipulation could be recommended for treat-
ment of episodic or chronic migraine and for cervico-
genic headache, and that no recommendations could
be made for treatment of tension-type headache. The
authors state that “adverse events were not addressed
in most clinical trials; and if they were, there were none
or they were minor.” These two studies illustrate some
of the differences between recommendations made by
physicians and by chiropractors. In brief, there are no
good quality studies suggesting benefit from spinal
manipulation, and studies showing benefit are limited
by methodologic weaknesses. In clinical practice, there
are anecdotal reports of patients who have improve-
ment in their headaches after spinal manipulation.
This patient was told that anecdotally some patients
report improvement in their headaches with chiro-
practic treatments but that the studies have not sup-
ported it as a treatment.
What should he be told about risks
associated with spinal manipulation?
Spinal manipulation has been associated with risks
ranging from minor to major. In a prospective case
154
series of patients treated with spinal manipulation,
minor adverse effects were reported by 30–60% of
patients and included neck pain, stiffness, headache,
and fatigue. In retrospective and case–control studies,
more dangerous outcomes included disc herniation,
vertebral fracture, dural tear, and, perhaps of most
concern, VAD. (Carotid artery dissection is reported
much less frequently than VAD, likely because the
carotid artery is not tethered in the cervical region and
therefore moves more freely.)
Several case–control studies have shown a relation-
ship between spinal manipulation, whether by chiro-
practors or other practitioners (orthopedic surgeons,
shiatsu practitioners), and VAD. One case–control
study showed that patients with VADs were more likely
to report previously having chiropractic upper spinal
manipulation than those with carotid artery dissection
(6% vs. 30%). Dissection of both vertebral arteries was
also linked to spinal manipulation. In another case–
control study, the odds of developing a VAD were five
times higher within one week after a chiropractor visit
in patients under the age of 45. These cases with VAD
were also five times more likely to have seen a chiro-
practor three or more times in the last month for a cer-
vical diagnosis.
Other studies have suggested a possible alternative
interpretation for these data, however. A large case–
control and case-crossover study of the population
of Ontario evaluated risk for VAD or vertebrobasilar
stroke as a function of visits to the chiropractor or to
the primary care physician. In this study, cases under
the age of 45 were three times more likely to have vis-
ited their primary care physician and three times more
likely to have visited a chiropractor in the month prior
to the stroke. There was no association for cases over
the age of 45.
The authors of this study and others note that
VAD often presents with headache and neck pain.
Because of this, patients may present to a chiroprac-
tor or to their primary care physician for these symp-
toms before they are finally diagnosed. It may there-
fore be difficult to assess whether the increased risk
noted by the case–control studies is simply a reflec-
tion of usage of chiropractic care for a pre-existing con-
dition, rather than the chiropractic care causing that
condition. As one chiropractor summed up the results
of this study: “You are no more likely to have a dis-
section walking out of my office than out of your pri-
mary care physician’s office.” Our practice is to edu-
cate patients about the risks of VAD associated with

chiropractic treatment when the issue is discussed at
an office visit.
Discussion
VAD has an incidence of about 1.5/100 000 and often
presents with headache and neck pain. The concern
about adverse effects from spinal manipulation was
initially raised in the 1990s after reports of two deaths
due to artery dissection after neck manipulation. Since
these initial reports, the question of how much risk
for cervical artery dissection is attributable to spinal
manipulation has been hotly debated. VADs are more
common in the cervical regions than carotid artery
dissections. The vertebral artery is highly susceptible to
trauma due to torsion particularly at the C1–C2 junc-
tion, where it wraps around the atlas prior to enter-
ing the cranium. VAD is caused by a hematoma in the
vessel wall, and may be spontaneous or, more com-
monly, associated with trauma of some kind. VAD has
been attributed to sudden neck movements associated
with spinal manipulation, but also with sport activi-
ties such as volleyball, heavy lifting, dental examina-
tion, turning the head while driving, or a prolonged
episode of coughing. There is also a case report of a
patient who regularly “cracked” her neck due to neck
pain and developed a VAD.
There are several mechanisms by which a VAD can
lead to stroke or other neurologic deficits. The expand-
ing intramural hematoma may occlude the lumen of
the vertebral artery or one of its branches. If the
hematoma expands outward, adjacent structures may
be compromised. Lastly, dissection of the high cervical
vertebral artery may also be associated with thrombo-
sis leading to embolic infarcts. It is probably safe to say
that data regarding the risks of VAD associated with
spinal manipulation are conflicting, and given the sig-
nificant degree of morbidity associated with VAD it is
probably safest to avoid this treatment until more is
known.
Diagnosis
Tension-type headache vs. cervicogenic headache.
Tip
Chiropractic treatments for headache and neck pain
do not have proven efficacy and may be associated with
increased risk for serious adverse events such as VAD.
Patients should be educated about these risks.
Chapter 9: Pitfalls in nonpharmacologic treatment
A pregnant woman with cluster
headaches
Case
A 26-year-old woman was seen in the headache clinic
because of severe headaches that started two weeks
ago. Three years ago she experienced a two-month
episode of daily or near-daily headaches similar to
her current headaches. The headaches were located
behind the left eye and were extremely severe, although
they lasted just 45 minutes to an hour. They recurred
nightly, usually an hour or so after she fell asleep.
Headaches were associated with tearing of the left
eye and stuffiness of the left nostril. The patient had
sought evaluation for these headaches. A CT scan of
the head was normal with the exception of some bilat-
eral mucosal thickening of the maxillary sinuses. She
was treated with antibiotics and decongestants but the
headaches had not improved. She was then scheduled
for sinus surgery but cancelled the operation when the
headaches spontaneously disappeared.
Two weeks ago these headaches began again, but
instead of coming just once a day they were occur-
ring up to four times a day. In the clinic, her neuro-
logic and physical examinations were normal. She was
in good health but was eight weeks pregnant and did
not wish to use any medications. She added, however,
that she was “desperate” and might consider terminat-
ing the pregnancy if medication treatment could not
be avoided.
What is the diagnosis, and what nondrug
treatments might be considered?
The history of severe, retro-orbital pain with associ-
ated autonomic features is consistent with a diagno-
sis of cluster headache. The patient’s attacks lasted 45
minutes, which is well within the typical range of 15
minutes to 3 hours for cluster headache. Furthermore,
they occurred at night shortly after she fell asleep, a
time that coincides with the usual onset of rapid-eye-
movement sleep. This “alarm clock” timing is charac-
teristic of cluster headache, which is sometimes con-
sidered a parasomnia because of its common occur-
rence during this phase of sleep.
Individual attacks of cluster headache are usually
treated with sumatriptan injections or inhalation of
100% oxygen at 7–12 liters using a nonrebreather face
mask. For this patient, oxygen is an attractive nondrug
155
 Chapter 9: Pitfalls in nonpharmacologic treatment
approach to the management of individual headaches.
It is somewhat cumbersome, however, and since this
patient has four headaches a day it is also desirable to
do something to try to prevent headaches or reduce
their occurrence.
Nondrug approaches to cluster headache preven-
tion include the use of implantable sphenopalatine
ganglion stimulators or attempts at peripheral nerve
blockade, typically blockade of the greater occipital
nerve on the side of the headaches. Peripheral nerve
blocks provide immediate analgesia of the territory
supplied by the targeted nerve, but for unclear reasons
they may also produce pain relief that persists for days
or even weeks after the short-term effects of the nerve
block wear off. Some speculate that this is due to inhi-
bition of central sensitization when painful peripheral
input into the central nervous system is interrupted.
The effectiveness of greater occipital nerve blockade
for the treatment of cluster headache is supported by
results from two double-blind, randomized controlled
trials.
How are greater occipital nerve blocks
performed, and how often can they be
repeated?
The greater occipital nerve supplies sensation to the
posterior portion of the scalp, and is a branch of
the second cervical nerve. Because it is relatively
superficial and easy to access in the posterior por-
tion of the head, greater occipital nerve blockade is
not a technically challenging procedure. Most experts
recommend that the position for the nerve block
is localized by imagining a line running between
two scalp landmarks: the occipital protruberance and
the mastoid process. The greater occipital nerve is
likely to lie approximately one-third of the distance
from the occipital protruberance on this line. The
occipital artery is usually located laterally to the
nerve, so palpation is important to avoid intra-arterial
injections.
Greater occipital nerve blockade may be done
using only a local anesthetic such as lidocaine 1–2%
or bupivacaine 0.25–0.5%, or a corticosteroid can be
added to the local anesthetic. The volume of local
anesthetic injected is usually 1–3 mL per injection.
The Peripheral Nerve Block Special Interest Section of
the AHS recommends that injections can be repeated
156
every 2–4 weeks depending upon patient response. In
our practice, we use a 5 mL syringe with a 27 gauge nee-
dle and 2 mL of 1% lidocaine. We typically do not use
corticosteroids unless patients do not have a response
to local anesthetic used alone. In pregnant patients
lidocaine is the local anesthetic of choice, since it
has an FDA use-in-pregnancy rating of B (compared
with C for the alternative choice of bupivacaine). We
also recommend avoiding the use of corticosteroids in
patients who are pregnant.
The patient in this case was given oxygen to use
for individual attacks of headache, and treated with left
greater occipital nerve block in an attempt to prevent
headaches. After her first injection she was headache-
free for ten days. The injection was then repeated, and
her headaches did not recur.
Discussion
Cluster headache is more common in men, but it
also occurs in women. Because it is less common
in women, physicians may be more likely to assume
that the headaches have other causes. In this case,
the headaches were initially misdiagnosed as a sinus
problem. Delayed and inaccurate diagnosis of clus-
ter headache is common in patients of both sexes,
however. Unfortunately, this patient’s experience is not
unusual. Cluster headache is often attributed to sinus
problems, which may then lead to unnecessary and
usually ineffective sinus surgery.
Pharmacologic management of cluster headaches
is usually highly effective. Most patients respond
well to subcutaneous sumatriptan, and verapamil or
lithium treatment often completely eliminates attacks.
Because these are the standard therapies for the disor-
der, it is easy to overlook nonpharmacologic treatment
options.
There are good reasons in this patient to avoid
the use of lithium and verapamil. She is in her first
trimester of pregnancy, when organogenesis is occur-
ring and teratogenic effects are most likely to occur.
Lithium use during pregnancy has been associated
with fetal cardiac malformations, and the high doses
of verapamil necessary to treat cluster headache effec-
tively would be likely to exacerbate pregnancy-related
edema and constipation. Thus, nondrug preventive
approaches to treatment such as the use of occipi-
tal nerve blocks are a first-line approach in pregnant
patients with cluster headache.

“Bridging” therapy with high-dose corticosteroids
is often used to bring cluster headaches under control
quickly until preventive medications become effec-
tive, but the safety of such treatment in pregnancy is
unknown. Likewise, although accumulated informa-
tion about sumatriptan suggests it is probably safe in
pregnancy, the number of reported pregnancy out-
comes is too small to rule out completely any residual
teratogenic risk of the drug. Oxygen inhalation, on the
other hand, is likely to be safe and is therefore the pre-
ferred method of abortive cluster headache treatment
in pregnancy.
Diagnosis
Episodic cluster headache during the first trimester of
pregnancy.
Tip
Although cluster headache is usually treated pharma-
cologically, it is important to remember that effec-
tive acute and preventive nonpharmacologic treatment
options exist. These are useful for patients who cannot
or do not wish to take medications.
A woman with migraine aura
who requests testing for a patent
foramen ovale
Case
A 29-year-old woman was seen in the headache clinic
with complaints of headaches associated with focal
neurologic deficits. Her headaches had begun dur-
ing her teenage years and increased in frequency
and severity in her 20s. Headaches were described
as throbbing and were associated with nausea. The
patient typically experienced two or three headache
days in an average month and they seemed to be espe-
cially common before the onset of menstruation. She
treated individual attacks of headache with 5 mg of
zolmitriptan. This was usually effective in eliminating
the headache and she rarely needed to re-dose.
Six months prior to being seen in clinic, she began
to experience typical visual and sensory aura symp-
toms consisting of numbness of her left hand and face.
These symptoms were stereotyped and occurred before
about a quarter of her headaches and never lasted more
Chapter 9: Pitfalls in nonpharmacologic treatment
than 40 minutes. An MRI scan of the brain showed
rare punctuate foci of T2 hyperintensity in the deep
frontal white matter regions bilaterally. She was on no
medications.
Her neurologic symptoms were felt to be consistent
with a diagnosis of migraine with typical aura, and no
change in her treatment regimen was advised. Several
days after her consultation, however, the patient con-
tacted the headache clinic doctor. She had been read-
ing about migraine with aura on the internet and had
learned about a possible connection between this con-
dition and patent foramen ovale (PFO). She wondered
whether a PFO could be the cause of her problems and
if she should undergo testing for a PFO. She had read
that closure of a PFO could sometimes cure migraine,
and she was excited about the possibility of a perma-
nent “nondrug cure” for her migraine.
What is the relationship between migraine
with aura and PFO?
PFO is a common cardiac anomaly in which there is
an abnormal opening between the right and left atrial
chambers of the heart. PFO is thought to occur during
fetal life when the septal tissue between the two cham-
bers does not completely fuse. The resulting opening
is often quite small and is frequently covered by a flap
of tissue. Under normal conditions pressure is higher
in the left atrium than the right, and this holds the
flap closed. The flap can open, however, when there is
a sudden increase in pressure in the right atrium (for
example, when people cough, sneeze, or strain). Under
these circumstances blood from the right side of the
heart can be shunted to the left atrium without first
passing through the pulmonary circulation.
Autopsy studies suggest PFO occurs in roughly
a quarter of the normal population. It rarely causes
problems and usually does not come to medical atten-
tion. Since both PFO and migraine are common con-
ditions, their frequent co-occurrence is not surpris-
ing. What has led to interest in their connection, how-
ever, is the fact that the prevalence of PFO appears
to be increased in patients who have migraine with
aura beyond what would be expected by chance alone.
However, the magnitude and nature of the associa-
tion between PFO and migraine with aura remain
uncertain.
One possibility is that migraine and PFO share
a common underlying cause, perhaps an inherited
157
 Chapter 9: Pitfalls in nonpharmacologic treatment
connective tissue abnormality that predisposes a per-
son to both PFO and migraine. If that is the case, treat-
ment of one problem would not be expected to have an
effect on the other. Some investigators, however, have
proposed that a PFO might actually cause migraine
aura by allowing small emboli or vasogenic substances
from the systemic circulation to pass directly into the
cerebral circulation. Ordinarily these would be filtered
when blood passes through the pulmonary circulation.
According to this theory, these substances may then
trigger aura and headache, and could also be responsi-
ble for small ischemic insults that lead to cerebral white
matter changes.
Should patients who have migraine with
aura be evaluated for a PFO and possible
shunt closure?
Small case series and other observational studies sug-
gested that closure of PFOs, usually performed percu-
taneously, produced substantial improvement of aura
and headache. However, these studies had no con-
trol groups and were retrospective in nature. Addi-
tionally, most patients who underwent PFO closure
were treated with aspirin or clopidogrel following the
procedure. These things, along with the substantial
placebo effects associated with a procedure, could have
explained some or all of the apparent improvement in
migraine and aura with PFO closure.
A randomized, sham-controlled trial performed in
the United Kingdom evaluated the impact of PFO clo-
sure on migraine in 147 subjects who had migraine
with aura refractory to at least two classes of pro-
phylactic therapy. This study did not show a sta-
tistically significant difference between the sham or
actual PFO closure for the primary endpoint of the
trial, which was complete resolution of headaches.
Only three patients in each group had complete res-
olution of headaches over the three months follow-
ing the procedure. There were no major differences
between the true and sham surgery groups for other
prespecified secondary outcomes of the study. How-
ever, a post-hoc analysis that removed several subjects
with a large number of headache days from the anal-
ysis showed that subjects who underwent PFO clo-
sure had a reduction of 2.2 headache days per month
compared with a reduction of 1.3 headache days per
month in those who underwent the sham procedure.
This ambiguous result has left some experts interested
158
in further study of PFO closure for the treatment of
migraine.
Discussion
In our view, available evidence clearly demonstrates
an unfavorable balance between possible benefits and
harms from PFO closure for migraine with aura.
The UK randomized trial did not demonstrate con-
vincing benefits of closure. In contrast, a number of
adverse events occurred in the PFO closure group.
These included cardiac tamponade, pericardial effu-
sion, retroperitoneal hemorrhage, and atrial fibril-
lation. It is of concern that these events occurred
in the context of a carefully conducted clinical trial
in which PFO closure was performed by highly
trained, expert interventional cardiologists in carefully
selected, healthy patients with few comorbid condi-
tions. It is likely that the complication rate would be
higher if procedures were performed in the course of
usual care in a broader range of patients.
Meanwhile, mounting evidence shows no clear cor-
relation between the burden of white matter lesions
on brain MRI and the presence of a PFO. This fur-
ther weakens the argument that the presence of a PFO
might lead to ischemic or embolic events that could
produce aura or other lasting events. It is interesting
to note that PFOs have also been suspected as a pos-
sible cause for ischemic stroke in young people with
no other apparent reason for stroke. Yet a recent study
failed to show any reduction in the risk of a second
ischemic stroke in patients with PFO who underwent
closure.
For all of these reasons, we do not recommend
searching for a PFO in patients who have migraine
with aura. In the case of the patient in the vignette,
whose headaches are well controlled with abortive
therapy alone, there is even less reason to pursue a
workup for PFO.
Diagnosis
Migraine with typical aura.
Tip
Available evidence does not clearly support a causal
link between PFO and migraine with aura, and the
harms of PFO closure appear to outweigh the benefits.
Patients with aura should not undergo testing for the
presence of a PFO.

A young woman asking about
migraine surgery
Case
A 23-year-old woman was seen in the headache clinic
where she reported having headaches 20 or 25 days in
a typical month. Her headaches had started when she
was nine years old. They steadily worsened through
high school and college. About 10–15 days in an aver-
age month the patient had dull, bilateral pain over her
temples and forehead with no associated symptoms.
This pain was rated 5 on a 0–10 pain scale. The rest
of her headaches were more severe. These headaches
began in the posterior occipital region of her head
on the right side and radiated forward to the right
temple. She also reported shock-like pain in her face,
jaw, and cheek on the right. Headaches were associ-
ated with nausea and photo and phonophobia. She
could not identify any clear triggers or relieving factors
for her headaches. Examination and workup had been
negative.
She was diagnosed with chronic migraine. Trip-
tans were tried but were only partially effective for
some headaches. Multiple trials of preventive medi-
cations including beta-blockers, tricyclic antidepres-
sants, antiepileptic medications, and botulinum toxin
injections had not been helpful or had produced intol-
erable side effects.
The patient had experienced difficulty forming suc-
cessful long-term relationships with caregivers. She
was bitter that doctors had not been able to cure her
headaches. She was starting to miss work at a new job
and was very concerned. At her visit she asked whether
she would be a good candidate for the new “migraine
surgery” she had heard about on the news.
What is the “migraine surgery” this patient
is referring to?
Over the last decade the idea of a surgical “solution”
to migraine has been popularized by plastic surgeons,
reportedly inspired by headache improvement that
was serendipitously noted in patients who underwent
cosmetic “forehead rejuvenation” procedures. Because
the plastic surgery procedures involved removal of
muscles in the forehead, a plastic surgeon developed
the idea that contraction of facial muscles might pro-
duce migraine by impinging on peripheral branches of
the trigeminal nerve.
Chapter 9: Pitfalls in nonpharmacologic treatment
The procedures performed to reduce this
“impingement” include resection of the corruga-
tor supercilii muscle with the placement of fat grafts
in the site. Some procedures involve dissection of
the glabellar area. Transection of the zygomatical
temporal branch of the trigeminal nerve is also
often performed. In cases of posterior pain the
semispinalis capitus muscle may be resected with
placement of fat grafts in the area, with the aim of
reducing pressure on the occipital nerve. Finally, some
surgeons also perform nasal septoplasty or other-
wise attempt to address possible intranasal trigger
points.
The procedures involved are often referred to col-
lectively as “migraine deactivation surgery” (MDS),
although as described above a variety of surgical sites
and procedures are involved. The approach to each
patient is typically individualized, making it difficult
to study outcomes objectively. Patients who fail to
improve with surgery are often told that they need
more surgery to deactivate other trigger points that
were “missed” the first time around. Many plastic sur-
geons who do this form of surgery select patients for
surgery on the basis of improvement in headaches with
the injection of onabotulinumtoxinA and/or occipital
nerve blockade, on the theory that response to such
temporary procedures is proof of nerve impingement.
How strong is the evidence of benefit from
migraine surgery?
Various uncontrolled observational studies have been
published that report impressive success with MDS,
and two randomized trials have been performed.
Unfortunately, proponents of the surgery have per-
formed all of these studies and nearly all were pub-
lished in a single plastic surgery specialty journal. The
two trials suffered from serious methodologic prob-
lems that limit the conclusions that can be drawn from
them. Taken as a whole, the evidence base for MDS is
remarkably weak.
Despite this MDS is becoming more common. A
recent survey of members of the American Society of
Plastic Surgeons found that 18% of respondents had
performed migraine surgery. Of those who had not
performed the surgery, 60% said they “would be inter-
ested if an appropriate patient was referred to them by
a neurologist.”
For these reasons, the AHS has issued a state-
ment urging “patients, healthcare professionals and
159
 Chapter 9: Pitfalls in nonpharmacologic treatment
migraine treatment specialists themselves, to exercise
caution in recommending or seeking such therapy.”
This statement went on to say that “In our view, surgery
for migraine is a last-resort option and is probably
not appropriate for most sufferers. To date, there are
no convincing or definitive data that show its long-
term value. Besides replacing the use of more appro-
priate treatments, surgical intervention also may pro-
duce side effects that are not reversible and carry
the risks associated with any surgery. It also can
be extremely expensive and may not be covered by
insurance.”
Discussion
Unfortunately, there are no cures for migraine and
some patients with chronic migraine do not bene-
fit from currently available treatments. It is easy to
understand why the patient in this vignette is so inter-
ested in a potential nondrug, surgical approach to
migraine treatment. However, surgical treatments for
migraine have a long and undistinguished history and
have not stood the test of time. “Migraine deactivation
surgery” seems unlikely to be an exception to this pat-
tern. In the early twentieth century some surgeons per-
formed cervical sympathectomies for migraine, ligated
the external carotid artery, or carried out various de-
afferentation procedures on branches of the trigeminal
nerves.
Despite unconvincing evidence of benefit and cau-
tions from experts, MDS has received extensive and
favorable coverage in the popular press, and anecdo-
tal stories of patients with dramatic improvement in
migraine are easy to find on the internet. Unfortu-
nately, in our practice we have seen patients with poor
outcomes following surgery, and reports of serious
adverse events are also appearing online.
At this point it is difficult to predict who may have a
good outcome from surgery for treatment of migraine
and it remains experimental therapy. There are signif-
icant risks with any surgery, including cranial nerve
injury and worsened long-term pain. The risks of MDS
have not been well characterized or quantified by inde-
pendent researchers. In our view, this surgery should
only be performed in the context of a well-designed
randomized sham-controlled trial. If this surgery turns
out to have serious long-term complications, physi-
cians who have referred patients for this treatment
could face legal liability.
160
Diagnosis
Chronic refractory migraine.
Tip
Migraine deactivation surgery is not well studied as
a treatment for migraine and remains experimental.
Patients should be informed about the uncertain bal-
ance of benefits to harms and the potential for irre-
versible adverse effects.
Recommended reading
Food triggers for migraine
Panconesi A, Bartolozzi ML, Guidi L. Alcohol and
migraine: what should we tell patients? Curr Pain
Headache Rep. 2011;15(3):177–84.
Rockett FC, de Oliveira VR, Castro K, et al. Dietary aspects
of migraine trigger factors. Nutr Rev. 2012;70(6):337–56.
Other triggers for migraine
Andress-Rothrock D, King W, Rothrock J. An analysis of
migraine triggers in a clinic-based population.
Headache. 2010;50(8):1366–70.
Martin PR. Behavioral management of migraine headache
triggers: learning to cope with triggers. Curr Pain
Headache Rep. 2010;14:221–7.
Martin PR, MacLeod C. Behavioral management of
headache triggers: avoidance of triggers is an inadequate
strategy. Clin Psychol Rev. 2009;29:483–95.
Nicholson RA, Buse DC, Andrasik F, Lipton RB.
Nonpharmacologic treatments for migraine and
tension-type headache: how to choose and when to use.
Curr Treat Options Neurol. 2011;13(1):28–40.
Behavioral treatments
Andrasik F. What does the evidence show? Efficacy of
behavioural treatments for recurrent headaches in
adults. Neurol Sci. 2007;28:S70–7.
Campbell JK, Penzien DB, Wall EM. Evidence-based
guidelines for migraine headaches: behavioral and
physical treatments. 2000. Retrieved from http://www.
aan.com/.
Nicholson RA, Buse DC, Andrasik F, Lipton RB.
Nonpharmacologic treatments for migraine and
tension-type headache: how to choose and when to use.
Curr Treat Options Neurol. 2011;13(1):28–40.
Smitherman TA, Penzien DB, Rains JC. Challenges of
nonpharmacologic interventions in chronic tension-type
headache. Curr Pain Headache Rep. 2007;11:471–7.

Vitamins, supplements, and herbal treatments
for migraine
Evans RW, Taylor FR. “Natural” or alternative medications
for migraine prevention. Headache. 2006;46(6):1012–
18.
Maizels M, Blumenfeld A, Burchette R. A combination of
riboflavin, magnesium, and feverfew for migraine
prophylaxis: a randomized trial. Headache. 2004;
44(9):885–90.
Mauskop A. Nonmedication, alternative, and
complementary treatments for migraine. Continuum
(Minneap Minn). 2012;18(4):796–806.
Physical therapy
Chaibi A, Russell MB. Manual therapies for cervicogenic
headache: a systematic review. J Headache Pain.
2012;13:351–9.
Jull G, Trott P, Potter H, et al. A randomized controlled trial
of exercise and manipulative therapy for cervicogenic
headache. Spine. 2002;27(17):1835–43.
Sjaastad O, Bakketeig LS. Prevalence of cervicogenic
headache: Vågå study of headache epidemiology. Acta
Neurol Scand. 2008;117(3):173–80.
Chiropractic treatments for headache
Bryans R, Descarreaux M, Duranleau M, et al. Evidence-
based guidelines for the chiropractic treatment of adults
with headache. J Manipulative Physiol Ther.
2011;34(5):274–89.
Cassidy JD, Boyle E, Côté P, et al. Risk of vertebrobasilar
stroke and chiropractic care: results of a population-
based case-control and case-crossover study.
J Manipulative Physiol Ther. 2009;32(2 Suppl):S201–8.
Ernst E. Adverse effects of spinal manipulation: a systematic
review. J R Soc Med. 2007;100(7):330–8.
Posadzki P, Ernst E. Systematic reviews of spinal
manipulations for headaches: an attempt to clear up the
confusion. Headache. 2011;51(9):1419–25.
Chapter 9: Pitfalls in nonpharmacologic treatment
Nerve blocks
Ashkenazi A, Blumenfeld A, Napchan U, et al. Peripheral
nerve blocks and trigger point injections in headache
management – a systematic review and suggestions for
future research. Headache. 2010;50(6):943–52.
Blumenfeld A, Ashkenazi A, Napchan U, et al. Expert
consensus recommendations for the performance of
peripheral nerve blocks for headaches – a narrative
review. Headache. 2013;53(3):437–46.
PFO and migraine with aura
Davis D, Gregson J, Willeit P, et al. Patent foramen ovale,
ischemic stroke and migraine: systemic review and
stratified meta-analysis of association studies.
Neuroepidemiology. 2013;40:56–67.
Dowson A, Mullen M, Peatfield R, et al. Migraine
Intervention with STARRFlex Technology (MIST) trial:
a prospective, multicenter, double-blind,
sham-controlled trial to evaluate the effectiveness of
patent foramen ovale closure with STARFlex septal
repair implant to resolve refractory migraine headache.
Circulation. 2008;117:1397–404.
Furlan AJ, Reisman M, Massaro J, et al. Closure or medical
therapy for cryptogenic stroke with patent foramen
ovale. N Engl J Med. 2012;366:991–9.
Tepper S, Cleves C, Taylor F. Patent foramen ovale and
migraine: association, causation, and implications of
clinical trials. Curr Pain Headache Rep. 2009;13:
221–6.
Migraine surgery
Gaul C, Holle D, Sandor PS, et al. The value of “migraine
surgery”. Overview of the pathophysiological concept
and current evidence. Nervenarzt. 2010;81(4):463–70.
Guyuron B, Reed D, Kriegler JS, et al. A placebo-controlled
surgical trial of the treatment of migraine headaches.
Plast Reconstr Surg. 2009;124(2):461–8.
Kung TA, Pannucci CJ, Chamberlain JL, Cederna PS.
Migraine surgery practice patterns and attitudes. Plast
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161
 Chapter
Challenges and special situations in
10 headache management
Dr. John R. Graham, who founded our headache cen-
ter, wrote in 1955 that “The successful treatment of
migraine is difficult but worth the effort. It taps every
resource of the physician. Probably more hours of
suffering are caused by migraine than by any other
human affliction. Knowledge of its secrets is incom-
plete but increasing. For these reasons it presents a
unique challenge.” We find these words are as true
today as when they were written, and they apply to all
headache types, not just migraine. We devote the first
part of this chapter to some of the more challenging
situations that may arise in the care of a patient with
headache. These include mismatches between patient
and physician goals or expectations, requests for opi-
oid treatment, refractory medication overuse, psychi-
atric comorbidities, and managing the many risk fac-
tors that can come together to worsen headache over
time. At times it can be difficult to fully engage patients
as active participants in their care, although a wealth
of research shows that such a shared decision-making
approach is the best treatment model for chronic con-
ditions such as headache.
In all of these situations, there are steps physicians
can take to increase the likelihood of a positive out-
come. In this chapter, we aim to provide some sug-
gestions about how to foster a therapeutic doctor–
patient relationship, set clear boundaries, promote
shared decision-making, and avoid some of the com-
mon pitfalls in managing these most difficult presen-
tations of headache.
Lifelong migraine refractory to
multiple treatments
Case
A 44-year-old man sought treatment for chronic
headaches. He reported he has had headaches since he
was a teenager and “I have tried everything and noth-
162
ing seemed to help a whole lot, although a couple of
them worked for a year or so.” Upon questioning, he
could not recall the doses or duration of most of the
medications he had used, although he was able to recall
the names of many treatments. Records from his pre-
vious physician were handwritten and it is difficult to
decipher the notes. After review of his history and neu-
rologic examination, as well as the results of past test-
ing, a diagnosis of chronic migraine was made. The
physician suggested that as part of his treatment plan
he should keep a record of the frequency and sever-
ity of his headaches and track his use of medication to
treat individual headache attacks. The patient reported
that he “used to keep a headache calendar but it was a
lot of work and frankly, doc, I couldn’t see the point.
Trust me; I’ll let you know when I’m doing better. I
don’t need a calendar to tell me that.”
How is this patient’s recall of headaches
likely to compare with diary information?
Diagnostic and therapeutic decisions about headache
treatment are made on the basis of information about
headache frequency, intensity, and disability as well as
medication response. Patient recall of headache activ-
ity is likely to be quite accurate over short periods of
time. One study compared patient recall of headache
frequency and intensity over a four-week period as
recorded in a daily diary with their general recall of this
information. Patient recall of headache frequency was
accurate when compared with detailed diary informa-
tion, but they recalled a higher intensity of headaches
compared with diary information.
The authors of this study concluded that patient
recall of headache intensity is not particularly good.
The accuracy of headache information over a period of
time longer than four weeks was not studied. It seems
unlikely that patient recall of headaches that occurred
in the distant past is particularly accurate, however.

This case illustrates the negative treatment implica-
tions of missing information about headache response
to treatment.
Would headache calendars or diaries be
helpful in headache diagnosis or treatment
here? Would paper or electronic diaries
be better?
One study evaluated the performance of a basic diag-
nostic headache diary for diagnosis of tension-type,
migraine, and medication overuse headache in a num-
ber of European and Latin American countries. Sub-
jects were randomized to receive the diary at least a
month before their first visit to the headache center
or to receive it at the first visit. In 98% of cases who
received the diary before their first visit, information
in the diary was complete and together with the clinical
history was sufficient to make a definitive diagnosis. In
contrast, among subjects who had not completed one
month of diary recordings prior to the first visit, a diag-
nosis could be made in only 87% of cases. The authors
concluded that a headache diary did improve diagno-
sis of headache.
Another study evaluated acceptance of and com-
pliance with an electronic headache diary compared
with a traditional paper headache diary in a group of
headache patients diagnosed with medication overuse
headache. At the onset of hospitalization for medica-
tion withdrawal, patients were asked to keep both an
electronic and paper diary. Compliance with both was
good but patients felt the electronic diary was easier to
use.
However, another experiment assigned patients
with chronic pain (not headache) to use either a paper
diary with a hidden means of tracking use, or an elec-
tronic diary with time-stamped entries. Although the
paper diaries submitted by participants were com-
plete in 90% of cases, monitoring indicated that actual
compliance with assigned timing of entries was only
11%, suggesting “a high level of faked compliance.”
The authors of this study concluded that their findings
“call into question the use of paper diaries and sug-
gest that electronic diaries with compliance-enhancing
features are a more effective way of collecting diary
information.”
In this case, the patient was recommended to keep
an electronic headache diary using a smartphone app.
He was educated about the above studies and the
Chapter 10: Challenges and special situations
physician also told him that it would be very difficult
to make treatment decisions without numerical data to
inform them. The patient agreed to keep the diary.
Discussion
An objective record of headache occurrence and med-
ication use is important in order to follow the clinical
course of headaches and evaluate the results of treat-
ment. It is difficult to think of any other therapeutic
situations in which global patient recall is accepted as
the best way to monitor the natural history or treat-
ment response of an illness.
While it is difficult to optimize headache treat-
ment in the absence of sufficient information from a
headache diary, there is also such a thing as too much
information. Some patients present with color-coded
spreadsheets with detailed information on headache
activity, weather, diet, and other factors. In most cases
it is beyond the ability of the physician – or the patient
– to extract meaningful lessons from this “information
overload.” Overly detailed diaries also may draw need-
less attention to somatic symptoms, so we recommend
that patients collect the minimum information nec-
essary to make treatment decisions. We recommend
keeping track of headache frequency (number of days
a month with headache) and peak headache intensity.
An ongoing record of medication intake is also helpful
but can usually be very quickly compiled. One simple
headache diary is shown in Figure 10.1.
There are of course elements of the patient experi-
ence that will not be captured in diary recordings, such
as absence from work or social roles or the need to visit
the emergency department for headache treatment.
Diaries will never supplant a good physician interview,
and it is important to corroborate diary findings with
other signs that a patient is improving or worsening,
including disability and absence from usual roles.
Diagnosis
Chronic migraine.
Tip
Accurate headache diagnosis and treatment planning
depend upon an accurate and permanent record of
headache activity and response to medication. In
most cases, patient recall is inferior to carefully kept
headache diaries.
163
 Chapter 10: Challenges and special situations

HEADACHE CALENDAR
MONTH:
DAYS MENSES INTENSITY (1–3 Mild, 4–6 Mod, 7–10 Disabling) ABORTIVE MEDICATION USED
ex P 1 2 3 4 5 6 7 8 9 10 N+S
1 1 2 3 4 5 6 7 8 9 10
2 1 2 3 4 5 6 7 8 9 10
3 1 2 3 4 5 6 7 8 9 10
4 1 2 3 4 5 6 7 8 9 10
5 1 2 3 4 5 6 7 8 9 10
6 1 2 3 4 5 6 7 8 9 10
7 1 2 3 4 5 6 7 8 9 10
8 1 2 3 4 5 6 7 8 9 10
9 1 2 3 4 5 6 7 8 9 10
10 1 2 3 4 5 6 7 8 9 10
11 1 2 3 4 5 6 7 8 9 10
12 1 2 3 4 5 6 7 8 9 10
13 1 2 3 4 5 6 7 8 9 10
14 1 2 3 4 5 6 7 8 9 10
15 1 2 3 4 5 6 7 8 9 10
16 1 2 3 4 5 6 7 8 9 10
17 1 2 3 4 5 6 7 8 9 10
18 1 2 3 4 5 6 7 8 9 10
19 1 2 3 4 5 6 7 8 9 10
20 1 2 3 4 5 6 7 8 9 10
21 1 2 3 4 5 6 7 8 9 10
22 1 2 3 4 5 6 7 8 9 10
23 1 2 3 4 5 6 7 8 9 10
24 1 2 3 4 5 6 7 8 9 10
25 1 2 3 4 5 6 7 8 9 10
26 1 2 3 4 5 6 7 8 9 10
27 1 2 3 4 5 6 7 8 9 10
28 1 2 3 4 5 6 7 8 9 10
29 1 2 3 4 5 6 7 8 9 10
30 1 2 3 4 5 6 7 8 9 10
31 1 2 3 4 5 6 7 8 9 10
Use P to indicate days of your menstrual period.
Use abortive medication abbreviations like T for Tylenol.
Combinations of medications like Naproxen and Sumatriptan can be written as N + S.

Figure 10.1 A simple headache calendar.

A patient with unrealistic expectations
Case
A 30-year-old female presented for evaluation of
headache and was accompanied by her mother. At the
start of the visit the patient stated “I’ve seen eight
doctors; you are the last one.” Her mother presented
the physician with copious records and noted that her
daughter had likely had her past medical care mishan-
dled and was now “at the end of her rope.” The patient

164

had left school and work due to headache; she was now
living at home and her major daily activity was con-
fined to walking the dog. She had had mild depression
in the past but was otherwise healthy.
At the end of the visit, the physician diagnosed
chronic migraine and made some suggestions for
treatment. Though she had extensive evaluation of her
headaches in the past, she and her mother expressed
their unhappiness that further testing was not sug-
gested. Multiple treatment options suggested by the
physician were rejected by the patient as having failed
in the past or having caused unacceptable side effects
or reactions. In some cases she had not tried the treat-
ment but was afraid that it would cause intolerable side
effects. At that point in the visit, she appeared to be
losing confidence in the provider. She then asked the
physician how she should treat her pain, as her prior
provider had only given her enough analgesic medi-
cation to get her to this appointment. She was frus-
trated by the provider’s response and both mother and
daughter left the office clearly unsatisfied.
What elements of the visit predicted a
suboptimal outcome?
While there is a great deal of variation in presenta-
tions of headache patients, and it can be difficult to pre-
dict how an individual patient will participate in their
care, certain elements of this patient’s presentation
were potentially troubling. These “red flags” include
the presence of a possibly codependent mother who
tended to take over the interview and speak for the
patient, multiple prior evaluations, and the comments
suggesting the presence of unrealistic expectations on
the part of the patient and family. While there are few
data on this topic, our experience has been that unre-
alistic expectations for benefit from treatment can be
one of the most significant barriers to effective care.
What could have been done to end this visit
on a more positive note?
The establishment of an effective and therapeutic
physician–patient relationship is the foundation for
headache treatment. This is especially true in cases of
refractory or particularly severe headache disorders,
and also when psychopathology plays a role in the
patient’s presentation. Both of these elements seem to
be at play in this case. Physicians can earn the trust
of patients by practicing active listening and demon-
Chapter 10: Challenges and special situations
strating empathy, eliciting patient goals for the visit
and addressing them specifically, educating the patient
about the nature of their diagnosis, being honest but
positive about likely benefits from treatment, and set-
ting boundaries. In this case, the patient and her
mother may have been more reassured if their specific
concerns were addressed.
Discussion
Addressing and managing patient expectations
for treatment can be a very challenging aspect of
headache medicine. While this issue is sometimes
an afterthought or not included at all in headache
education, this can make the difference between a
successful treatment relationship and a dysfunctional
one. Early recognition and management of unrealistic
expectations can at times change the outcome of a
visit.
One challenge is that headache seems uniquely
suited to self-diagnosis, with some patients insisting
that their headaches are caused by food disorders,
sinus disease, or an allergy condition, for example. In
the headache clinic, we also encounter patients fix-
ated on the idea that there is an as-yet undiscovered
structural problem underlying their headaches, which
the “right” test will reveal. Unless these concerns are
managed, patients are at high risk to be noncompli-
ant with suggested therapy, because in their view the
treatment does not address the cause of their symp-
toms. Patients sometimes decline headache medica-
tions because they do not want to mask pain until
the underlying cause is found. Other management
challenges include medication-seeking behavior and
the presence of comorbid psychiatric conditions, pri-
marily personality disorder. One particularly difficult
scenario is the patient who insistently asks for help
for their pain, but refuses all recommendations for
treatment.
When the problem is recognized early on, it may
sometimes be useful to dispense with the remain-
der of the medical history and instead explore with
the patient their assumptions, expectations, and fears.
When the provider is clearly unable to change the
course of the illness, messages that express the
provider’s wish that things could be different can
be supportive while simultaneously setting limits on
what the provider can offer. Concerning developments
in the history (e.g. overreliance by the patient on
one diagnosis) can be highlighted by the provider
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 Chapter 10: Challenges and special situations
expressing worry about the situation, but not blame
(e.g. “I worry that your focus on your sinus condition
could end up leaving another condition out of the pic-
ture.”). The result can be the forging of the basics of
a therapeutic relationship upon which the headache
problem can be further addressed. Lastly, the impor-
tance of referring patients for psychiatric evaluation
and treatment when indicated cannot be overstated.
This suggestion is more likely to be positively received
in the context of a good therapeutic relationship.
Diagnosis
Chronic migraine.
Tip
Failure to consider and address patient expectations in
every interaction, or to recognize and if possible man-
age unrealistic expectations up front, may lead to sub-
optimal outcomes.
Chronification of migraine in a patient
lost to follow-up
Case
A 24-year-old woman presented to the headache
clinic for evaluation of headaches meeting criteria
for migraine without aura. Headache onset was at
age 14, and at the time of her initial evaluation
she was having about seven headaches per month.
She was given oral sumatriptan and an antiemetic
for symptomatic therapy. At her follow-up appoint-
ment she reported increased headache frequency to
11 headaches per month, each treated with sumatrip-
tan, and she was started on amitriptyline for preven-
tive therapy. Despite recommendations to return to
clinic in six months, she was lost to follow-up for the
next two years, and when she next presented to the
clinic her headaches were now occurring 25 days per
month.
What may have contributed to the increased
frequency of this patient’s headaches?
Patients with high frequency episodic migraine (10–14
headache days per month) are at higher risk of transi-
tioning to chronic migraine than those with low fre-
quency episodic migraines, as might be expected. This
patient was therefore at higher risk for transitioning
166
Table 10.1. Risk factors for migraine chronification
Medical conditions
– Obesity
– Sleep disorders and snoring
– Depression
– Anxiety
– History of head or neck trauma
Lifestyle and habits
– Caffeine intake
– Poor response to life stress
– Medication overuse
– Headache-specific factors
– Frequent headache
– Presence of cutaneous allodynia
Non-modifiable factors
– Female sex
– Genetic predisposition
– Low educational level
– Low socioeconomic status
– Younger age
to chronic migraine. She had several other risk fac-
tors, however, including medication overuse, female
sex, and younger age. Upon further questioning, she
also revealed poor sleep which she had attributed to
ongoing anxiety, but her boyfriend had also told her
she snored. The risk factors for transition to chronic
migraine are listed in Table 10.1. Medication overuse is
a significant risk factor, as described elsewhere in this
book.
What could have been done to prevent the
transition to chronic migraine?
This case illustrates the importance of scheduling fre-
quent follow-up appointments while treatments are
being optimized. If the physician had been able to track
the increased frequency of headaches, a more aggres-
sive preventive regimen could have been initiated.
In patients with high frequency episodic migraine,
specifically evaluating risk factors for transition to
chronic migraine is appropriate. Some risk factors,
including age and sex, are not modifiable but may be
informative in determining risk. Treatment of modifi-
able risk factors may help prevent transition to chronic
migraine. The appropriate intervention is specific to
the risk factor. In this case, the patient could have
been referred to a sleep specialist to evaluate for possi-
ble sleep apnea. Anxiety can be specifically addressed
with cognitive behavioral therapy, or with appropriate
medication.

Discussion
About 3% of patients with episodic migraine, defined
as fewer than 15 headache days per month, transition
to chronic migraine, or having 15 or more headache
days per month, each year. Some risk factors for tran-
sition cannot be modified, but many risk factors can
be reduced or eliminated. The treatments are specific
to the risk factors. Stress and psychiatric diagnoses
may respond to behavioral therapy or biofeedback.
Obstructive sleep apnea is one of the easiest comor-
bidities to treat once the diagnosis has been made.
Although obesity, on the other hand, is notoriously
difficult to treat, patients can be referred for nutrition
and exercise programs to support weight loss. Emerg-
ing data from small prospective samples suggest that
gastric bypass may improve migraine. Dietary triggers,
including caffeine use, can be reduced.
Because medication overuse is such a strong risk
factor for migraine chronification, close monitoring of
headache frequency and symptomatic medication use
is important. When patients transition from low fre-
quency episodic migraine to high frequency episodic
migraine, active measures to reduce headache fre-
quency are in order. These can include starting a
preventive pharmacologic agent, lifestyle modifica-
tion, complementary and alternative treatments, and
biofeedback. Patients should also be counseled on the
factor leading to transition to chronic migraine and
invited to be active partners in reducing headache
frequency.
Because of the need to monitor symptomatic med-
ication use, headache frequency, and risk factors for
transition to chronic migraine, we recommend regu-
lar follow-up for all patients taking prescription med-
ications for migraine. While there are no guidelines
established, our practice is to see patients every 6–12
months while we are writing prescriptions. At these
follow-up visits, we assess these risk factors and try to
address any potentially problematic issues that arise.
Diagnosis
Chronic (transformed) migraine.
Tip
Transition from episodic to chronic migraine is more
common in patients with high frequency episodic
migraine. Some risk factors for transformation are
modifiable and should be addressed in at-risk patients.
Chapter 10: Challenges and special situations
A patient requesting early refills
Case
A 37-year-old man with chronic migraine called the
office on a Friday afternoon to request a prescrip-
tion for oxycodone/acetaminophen tablets. He had last
been seen for an office visit a month prior. At that
visit his preventive medications were adjusted, he was
asked to keep a headache diary to monitor headache
frequency and medication use, and he was given a pre-
scription for 18 zolmitriptan tablets (with 3 refills) to
treat individual attacks of headache. He was also given
30 tablets of hydrocodone to use as rescue medica-
tion for attacks of headache that did not respond to
zolmitriptan. The physician reviewed the concept of
medication overuse headache with him and asked him
to limit treatment of individual attacks to no more than
two or three days a week. He was also told that the 30
tablets of hydrocodone were to be used conservatively
and should last for at least six months, and that the
practice did not refill opioid prescriptions outside of
regular office visits.
At his follow-up visit the patient said that he had
used up the hydrocodone tablets he was given. The
zolmitriptan was effective but he had run out of it and
“the pharmacy won’t give me any more unless you call
to say it is okay.” He admitted that he had been tak-
ing these medications on a daily basis, but insisted that
he had many important things going on at work and
could not afford to have a headache. He pleaded for
the physician to prescribe oxycodone/acetaminophen
“just this once” because he believed it would more
effectively treat his pain. He added that he finds it hard
to believe anyone should have to suffer so much given
all of the strong medications that are available to treat
pain.
Are this patient’s treatment goals realistic?
This patient is clearly overusing his short-acting
headache medications, and is not compliant with pre-
viously agreed limits on medication use. The treat-
ment imperative that most patients feel when faced
with severe pain, when paired with daily or near-
daily headaches, is probably the biggest management
challenge in headache medicine. Disagreement about
the amount and type of medication allowed for acute
episodes of pain can be an ongoing source of ten-
sion between doctor and patient. Despite this, one of
the most important duties in managing patients with
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chronic headache disorders is to set safe and appropri-
ate limits on treatments used for individual headaches.
The need to limit use of short-acting pain relief
medications is the main point of difference between
the treatment of patients who have infrequent
headache attacks and those who have daily or near-
daily headaches. In patients whose attacks of headache
are relatively infrequent – typically less than one
attack a week – it is reasonable to expect that acute
treatment will return the patient to their baseline level
of function and eliminate pain. Early, aggressive treat-
ment of individual attacks of headaches, sometimes
using powerful medications, is the strategy most likely
to achieve these goals.
These objectives, however, are not realistic in
patients who have frequent headaches. In fact, overuse
of medications that produce good short-term pain
relief may paradoxically lead to worsening headache
over time, a situation known as medication overuse
headache. In patients with frequent headache, treat-
ment goals for individual headache attacks typically
must be adjusted: complete pain relief may not be
possible and return to baseline function may not
be achievable in all attacks. Instead, it is necessary
to balance the desire for short-term pain relief with
the longer-term goal of preventing disease progres-
sion and complications. Patients with frequent attacks
may have to pick and choose which attacks they treat
aggressively. Less convenient but more effective non-
oral medications with a higher short-term side effect
burden may be needed.
What are reasonable limits on medication
use? How much medication is “too much” or
“too frequent” when it comes to treating
individual attacks of headache?
The exact amount and type of medication that can pro-
duce medication overuse headache is unclear. There
is no definite evidence of an amount below which no
one will have problems and above which everyone
will. Rather, the susceptibility to medication overuse
headache probably exists on a continuum. Because we
do not know what the threshold is to produce medica-
tion overuse headache in an individual patient, we err
on the side of conservative recommendations. A typi-
cal rule of thumb is that medications to treat individ-
ual headaches – whether they be triptans, nonsteroidal
anti-inflammatory drugs (NSAIDs), opioids, or other
168
drugs – should not be used more than two or three days
a week. That’s days of use, not doses.
Particularly in specialty practice, there may be sit-
uations where deviation from this limit is defensible or
the best that can be accomplished, but this is a decision
to make only after usual attempts at treatment have
been tried.
What is the best way to handle this patient’s
request for medication?
Whatever rules are in place, not all patients will adhere
to them. Quickly and firmly addressing the matter will
help reduce misaligned expectations. Regular review
and reinforcement of medication limits will have a
longer-lasting impact. Doctors and patients who plan
regular follow-up visits to monitor medication use will
likely fare better than those who leave this to chance or
individual motivation.
The best response to this patient’s request is there-
fore to remind him of agreements about medication
use and ask him to schedule an office visit where you
might discuss alternative ways to treat his headache.
One strategy that may help defuse tension is to con-
sider a trial of medications that probably do not cause
medication overuse headache even when used fre-
quently. Some examples are listed in Table 10.2. Even
if these strategies are not effective for extremely severe
headaches, they may satisfactorily treat less severe
headaches and thus “spare” more potent and problem-
atic drugs for less frequent use.
Discussion
Treatment of chronic headache conditions is fre-
quently characterized by a tension between the desire
to relieve individual headaches and a need to prevent
the development of medication overuse headache. We
use the term “treatment imperative” to refer to the
compulsion to treat severe pain that most headache
patients experience. Even in the presence of substan-
tial side effects and long-term harms from the overuse
of symptomatic medications, patients and their doc-
tors often continue to pursue aggressive treatment of
individual headache episodes. It can be difficult for a
physician to enforce reasonable limits on medication
use, however, as doctors naturally feel an obligation to
administer some sort of treatment to relieve pain and
suffering.
 Chapter 10: Challenges and special situations

Table 10.2. Options for acute treatment of headache with a It is difficult to say to suffering patients that they
low risk of causing medication overuse headache
must limit the use of medications that effectively treat
Treatment Sample doses and formulations an individual headache in order to obtain long-term
Baclofen 10–20 mg orally up to three times daily benefits. Still, it is important that everyone involved
Diphenhydramine Orally or 25–50 mg IM or IV up to three realize that the patient will need to pick and choose
times daily which headaches they treat, and may need to accept
Hydroxyzine 25–50 mg orally up to three times daily partial rather than complete pain improvement.
Lidocaine nasal drops ½– 1 mL of 4% lidocaine via dropper in
one or both nostrils every two hours as
needed
Diagnosis
Neuroleptics (e.g. These drugs are useful parenterally in Medication overuse headache; chronic migraine.
promethazine, the emergency department; on an
chlorpromazine) outpatient basis we prefer rectal
administration, e.g. promethazine Tip
suppositories 25 mg per rectum up to
three times daily
Failure to set and enforce limits on the amount and
type of medication used to treat individual attacks of
NSAIDs Indomethacin as a rectal suppository is
often remarkably effective for severe headache is a common cause of poor treatment out-
headaches. We use 50 mg per rectum comes in patients with frequent headaches.
up to three times daily. Gastrointestinal
side effects make long-term use
problematic. Ketorolac is available for
oral use but also available as a nasal
A woman requesting treatment
spray and in preloaded syringes for IM
administration
with opioids
Occipital nerve blocks Case
Steroids Use must be limited, but to abort A 34-year-old woman consulted a physician about
prolonged headache we use 4 mg
orally twice daily for three days or a 20-year history of frequent, disabling migraine
15 mg IV (one time dose) headaches that have not responded well to treatment.
Tizanidine 2–6 mg orally up to three times daily She had relocated from out of state and was establish-
Trigger point
ing medical care. She brought past medical records
injections that document prior unsuccessful treatment trials with
a large number of preventive drugs for migraine. The
doses and duration of these trials appeared to have
Chronic headache disorders, however, are condi-
been adequate, but headaches continued to be dis-
tions of long duration that are not amenable to cure.
abling. She was allergic to triptans and had been told
Expectations must be adjusted in patients with very
she could not use NSAIDs because of gastric bypass
frequent headaches. The same self-care rehabilitative
surgery. She reported that oxycodone was helpful for
philosophy applied to other chronic pain conditions
headaches and that her prior physician provided her
is relevant in headache: immediate pain relief is not
with a prescription for 120 tablets a month. Her neu-
the goal in management of chronic pain, and patients
rologic examination was normal. Neuroimaging done
should be helped to realize that “hurt does not mean
in the last year was also normal. She requested that the
harm.” In some cases the problem is compounded by
physician continue her oxycodone prescription.
patient inability to tolerate any level of pain or distress.
The stark urgency of an individual headache, which is
reducible with medication, means that the standard of Should the physician continue her
practice is to focus on individual headaches. Unfor- oxycodone prescription? What important
tunately, for patients with frequent headaches this
misguided approach can lead to the ever-escalating information is missing in this case?
use of stronger and stronger medications for individ- We lack information about whether this patient has
ual headaches, with the paradoxical result that over risk factors for opioid misuse or has displayed previous
time headaches become worse and more difficult to behaviors consistent with opioid addiction or depen-
manage. dence. Problematic behaviors include such things as

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 Chapter 10: Challenges and special situations
unauthorized escalation of prescribed doses of opi-
oids, requests for early refills, or instances of lost
prescriptions. A conversation with her previous pre-
scribing physician would be very useful in identifying
whether any of these things have been problems in the
past.
It is also unclear whether the use of opioids has
improved the patient’s headache problem or her ability
to function. Frequent use of symptom-relieving med-
ications such as opioids or triptans is associated with
paradoxical worsening of headache in some cases, a
situation known as medication overuse headache. Pain
relief is an important goal of headache therapy, but so
is return to normal activities, including work. If this
patient’s ability to function has not improved or has
worsened, then continued use of opioids may not be
a good treatment choice.
How can a patient’s risk for opioid misuse,
addiction, or dependence be assessed?
There is no completely reliable way to determine if
patients will misuse opioids or develop addiction or
dependence syndromes. It is possible, however, to
identify patients who are at high risk of develop-
ing problematic drug-related behaviors in the future.
One commonly used tool, which is validated for
use in pain patients, is the Opioid Risk Tool. Based
on self-report about personal and family history of
substance abuse, sexual abuse, sex, age, and psy-
chiatric comorbidity, patients are identified as low,
medium, or high risk to develop problems with opioid
treatment.
In this case, a telephone call to the patient’s prior
prescribing physician revealed that the patient had a
long history of daily headache that had responded
poorly to treatment, and there had been no appar-
ent worsening of headaches after oxycodone treatment
was started. The physician reported, though, that he
had become increasingly uncomfortable prescribing
opioids for this patient. He noted that despite sev-
eral increases in the amount of oxycodone the patient
was allowed to use on a monthly basis, she remained
on social security disability for headache and sought
emergency department treatment for headaches sev-
eral times a month. Additionally, when screened with
the Opioid Risk Tool this patient reported a prior per-
sonal history of alcohol abuse, depression, and sexual
abuse at age five by a stepfather.
170
Discussion
This patient reported a long history of migraine head-
aches refractory to numerous appropriate attempts at
treatment. Refractory migraine is a common and vex-
ing problem, and not all patients respond to aggres-
sive attempts at treatment. Research is limited about
the use of maintenance opioid therapy to treat such
patients, but suggests that only a minority of patients
achieve long-lasting benefit. Meanwhile, evidence is
emerging to suggest that long-term opioid therapy can
be associated with harms such as the development of
opioid-induced hyperalgesia.
The main considerations with this patient are
whether there is sufficient evidence of meaningful clin-
ical benefit from maintenance opioid therapy to war-
rant continuation of that treatment, and whether she
is at risk for the development of abuse or dependence
syndromes. The conversation with her prior prescrib-
ing physician shows there has been no meaningful
improvement in function with the regular use of opi-
oids. Her score on the Opioid Risk Tool also indi-
cated that she is at high risk of opioid abuse. Thus,
this patient is probably best managed using non-opioid
therapies.
Diagnosis
Chronic migraine.
Tip
It is possible to identify patients at high risk of misus-
ing controlled substances.
A patient with recurrent medication
overuse headache
Case
A patient returned to the headache clinic after being
lost to follow-up. One year ago, he had been able to dis-
continue his long-term use of a butalbital-containing
compound. He was taking six to nine tablets a day
and had relied on the drug for years, during which his
headaches had worsened. He had been diagnosed with
medication overuse headache. The patient followed a
weaning schedule and was started on amitriptyline for
prevention of headaches. He used eletriptan 20 mg to
treat up to two bad headaches a week. His previously
daily headaches were then recognizable as episodic

migraine. When he did not come back for subsequent
visits, it was assumed that his headaches were so much
improved that he no longer required specialty care.
The patient returned to the clinic one year later
accompanied by his wife. She said that since last year
his headache frequency had slowly increased and that
he had returned to the use of butalbital-containing
medication to treat his headaches. He then discontin-
ued amitriptyline since it did not seem to be working.
The butalbital was helpful at first but over time he had
needed more and more to keep his headaches under
control. He admitted that his primary care physician
had been prescribing the medicine for the last four
months but “she’s worried about how much I’m tak-
ing and won’t prescribe it any more. She gave me just
enough medicine to make it to this appointment.” He
was advised to discontinue daily use of butalbital again
and resume preventive therapy. He replied, “Oh doc-
tor, with my schedule and the pressure at my work, I
just can’t afford to do that and have a headache!” His
wife interrupted and said that if he did not have his
medicine, he would be unable to work.
What additional diagnosis is suggested by
this patient’s presentation?
This patient meets criteria for medication overuse
headache. He has a pre-existing headache disorder that
has worsened in the context of daily use of a medica-
tion known to produce medication overuse headache.
Furthermore, previous treatment has established that
his headaches improve when this medication is with-
drawn. However, this patient also displays features
consistent with dependence on medication, including
tolerance to the effects of the drug, taking the drug
in larger amounts than intended, failed attempts to
reduce drug use, and continued use despite the pres-
ence of a medical condition that is likely to be related
to drug use.
In this case, the patient’s dependence is likely
due to the interaction of a genuine medical prob-
lem (migraine) with behavioral features that may sig-
nal the presence of a complicating psychiatric disor-
der. Behavioral dynamics that contribute to relapse
in patients with medication overuse headache include
overreliance on drugs as the only way to handle
headaches, medication use in anticipation of pain, and
the use of medication to treat emotional distress or
anxiety. Joel Saper and colleagues have suggested that
medication overuse headache “is not a unitary phe-
Chapter 10: Challenges and special situations
Table 10.3. Warning signs that a patient’s care will be
challenging
r Blaming others for their problems or misuse of medications
r Noncompliant with treatment recommendations
r Discrepancy between pain ratings and observable behavior or
demeanor
r Enlistment of others to endorse requests for medication
nomenon.” They distinguish between simple (type 1)
and complex (type 2) medication overuse headache.
The latter term refers to patients whose medication
overuse headache is associated with comorbid psychi-
atric disorders and a history of relapse.
What additional clinical features suggest
that management of this patient will be
challenging?
It is not always possible to identify patients whose
care will be challenging, but certain warning signs and
indications should be heeded. Table 10.3 lists a num-
ber of warning signals that should be heeded, sev-
eral of which are present in this case. The patient has
demonstrated disagreement with treatment recom-
mendations through his nonadherence to prescribed
therapy and follow-up care. His wife, who speaks for
the patient, is overly solicitous and blames the doctor
rather than the headaches or medication misuse for the
possibility that the patient might miss work.
Discussion
Most patients with headache problems are eager to get
better and are compliant with treatment recommen-
dations. Others, however, are challenging to care for.
Their personal or medical situations are often com-
plex, with the result that they may not benefit from
or adhere to treatment. Some of the conditions that
make patients difficult to care for include drug or
alcohol dependence, personality disorders, or family
problems. It is not always possible to identify patients
whose management will turn out to be difficult, but the
signs and signals discussed here can sometimes pro-
vide an opportunity to intervene early to prevent later
problems.
In our experience, patients such as the one in this
case need a team approach. Their care is too much
for a single doctor, and ongoing psychiatric treatment
is important to maximize the chances that treatment
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 Chapter 10: Challenges and special situations
will be successful. Firm limit-setting is important, as is
confrontation about inappropriate behavior.
We often find it useful to remember and act on
the wise advice of Joel Saper and his colleagues at
the Michigan Head Pain and Neurological Institute
in Ann Arbor. His staff has years of experience deal-
ing on an inpatient basis with challenging and refrac-
tory headache patients who are referred from around
the country. In their chapter on inpatient strategies for
refractory migraine in the book Refractory Migraine,
Saper and colleagues suggest an approach such as the
following:
‘Your behavior is part of the problem.’ (Give exam-
ples). ‘It is a barrier to effective therapy. You reject
our recommendations and battle us for control. This
behavior is counterproductive and undermines the
basic trust that is required in order to help you. Med-
ical care is voluntary on both sides. Quite frankly,
I don’t have to be your physician if this unpleas-
ant behavior continues, and you don’t have to be my
patient if you don’t choose to be. If we can’t agree that
I am in charge of your case and you will be respect-
ful, communicative, and compliant, I will discontinue
care.’
Diagnosis
Migraine complicated by medication overuse head-
ache, drug dependence, and family dysfunction.
Tip
Be alert for signs or signals of problem patients. Pursue
a consistent, firm approach to treatment and insist that
the patient be involved in psychiatric care as a condi-
tion of treatment.
Medication agreements
Case
A 65-year-old female presented, accompanied by her
husband, for management of her chronic migraine.
Migraines had been episodic and rare for many years
and were well controlled with a butalbital-containing
medication. About ten years prior the headaches esca-
lated in frequency and butalbital use also slowly esca-
lated over time. At the time of the visit, she was using
four to five tablets daily and on this regimen had 15–
20 headache days per month. No other headache med-
ications had been tried as she was able to function well
172
while taking butalbital. Medical history was significant
only for a family history of alcoholism.
She was given a diagnosis of chronic migraine and
medication overuse headache and options for manage-
ment were discussed with her. She voiced clear under-
standing of the need to change her current method
of treating her headaches but was apprehensive about
reducing the dosage of butalbital. She nonetheless
agreed to a modest reduction as part of the overall
plan, in addition to starting topiramate for preven-
tion of headaches. At follow-up, however, she reported
minor cognitive side effects and had not increased the
dosage of topiramate as requested. She had also run
out of the butalbital tablets that had been prescribed.
She did not view this as a problem; instead, she and her
husband both repeatedly commented that she was suf-
fering, that she was entitled to an early refill of butal-
bital and that she should not be left without it. They
repeatedly refocused the discussion away from tra-
ditional management and sought assurance that her
access to butalbital would not be restricted.
Could a different approach to initial
management have led to a better outcome?
The patient and her husband initially appeared to be
motivated to treat her headache problem and readily
agreed to the treatment plan. Apart from a family his-
tory of alcoholism, no other risk factors for substance
abuse or misuse were identified. There was no indica-
tion of visits to multiple practitioners, multiple emer-
gency department visits, or history of misuse of prior
medications. For many patients like this, the problem
of medication overuse simply “goes away” when they
are provided with more effective and appropriate treat-
ment for headaches.
Because the physician initially thought that the
patient’s prognosis for improvement was good, he had
not asked the patient to sign a medication agreement.
In hindsight, this was probably a mistake. A written
treatment agreement, completed at the initial visit,
would have served as a clear record of the physician’s
expectations about medication use, and outlined the
conditions under which treatment would occur. This
might have led to a better outcome.
What is the best management at this point?
At the follow-up visit, the patient appeared to be
medication seeking, and her husband appeared to be

Table 10.4. Features of a typical medication agreement or
contract
Outlines patient responsibility to comply with recommended
doses and limits on medication
Documents discussion of the potential harms of treatment
Describes the fact that treatment goals are relief but not
elimination of pain
Summarizes the details of monitoring that will be used, for
example random urine drug testing
Lists the ways in which the patient should contact the office to
request refills
Specifies expected behavior, for example no abusive language
or behavior towards staff, compliance with referral for
behavioral or psychologic evaluation
Identifies the circumstances under which treatment will be
discontinued
codependent in her medication overuse. In this chal-
lenging setting, several options for treatment might be
pursued. One option is to recommend abrupt cessa-
tion of butalbital as a condition of continued treat-
ment. Another approach might be to formulate a treat-
ment agreement that outlines the responsibilities of the
patient and physician. These agreements are often par-
ticularly helpful when prescribing medications with
high potential for abuse or dependence.
Although agreements are not legal contracts they
do serve as a record of expected behavior and conse-
quences contingent upon these behaviors. The objec-
tive is to help ensure adherence to agreed-upon lim-
its of the medication with the goal of preventing mis-
use, abuse, or diversion. Most experts recommend that
these agreements be used routinely whenever poten-
tially abusable medications are prescribed, because it
can be very difficult to determine in advance which
patients are at high risk for aberrant drug-related
behavior. In this situation, a medication agreement
would put the patient “on notice” that infractions
could jeopardize her access to care and focus attention
on the management plan. It also makes it easier for the
caregiver to refuse any request to deviate from the plan.
Components of a medication agreement are described
in Table 10.4.
Discussion
Medication agreements have long been employed
when opioids or other chronic treatments with abuse
potential are used to treat headache or other nonmalig-
nant pain syndromes. Prototype agreements are widely
Chapter 10: Challenges and special situations
available on the internet and can be adapted to suit an
individual practitioner’s or patient’s situation.
Agreements have been criticized as paternalistic
and unduly restrictive. Some feel that agreements con-
tribute to the undertreatment of pain or stigmatize the
patient. On the other hand, although these agreements
are not legal contracts enforceable in a court of law,
they may protect physicians from legal liability in the
event of adverse events or claims of negligent man-
agement, although evidence to support that view is
lacking. Given widespread concern over the increase
in opioid prescribing, however, many healthcare sys-
tems recommend the use of agreements as part of a
care plan for patients who require these drugs. Medi-
cation agreements can be a useful part of efforts to sys-
tematize and coordinate patient care. It is certainly the
case that clear written policies and procedures can help
clarify management.
Specific issues, especially the possibility of med-
ication overuse headache, arise when dependence-
inducing drugs are used chronically to treat headache
conditions. Some experts have suggested that treat-
ment should be reserved for compliant, reliable
patients with moderate to severe pain, and prescribed
by an experienced provider who knows the patient
well. Relative contraindications to such therapy for
headache include major psychiatric disorders such as
psychosis, personality disorder, or somatoform disor-
der; prior addiction disorders; past legal issues related
to prescription drug abuse or diversion; or an at-risk
family environment that might be associated with an
increased risk of drug diversion.
Diagnosis
Chronic migraine; medication overuse headache.
Tip
Medication agreements in headache management can
benefit all parties and should be considered when
potentially dependence-inducing medications are in
use. It can be difficult to predict in advance when an
agreement will be required and agreements are likely
underused.
Further reading
Headache diaries
Allena M, Cuzzoni MG, Tassorelli C, Nappi G, Antonaci F.
An electronic diary on a palm device for headache
173
 Chapter 10: Challenges and special situations
monitoring: a preliminary experience. J Headache Pain.
2012;13(7):537–41.
Jensen R, Tassorelli C, Rossi P, et al.; Basic Diagnostic
Headache Diary Study Group. A basic diagnostic
headache diary (BDHD) is well accepted and useful in
the diagnosis of headache. a multicentre European and
Latin American study. Cephalalgia. 2011;31(15):
1549–60.
McKenzie JA, Cutrer FM. How well do headache patients
remember? A comparison of self-report measures of
headache frequency and severity in patients with
migraine. Headache. 2009;49(5):669–72.
Nappi G, Jensen R, Nappi RE, et al. Diaries and calendars
for migraine. A review. Cephalalgia. 2006;26(8):905–16.
Stone AA, Shiffman S, Schwartz JE, Broderick JE, Hufford
MR. Patient compliance with paper and electronic
diaries. Control Clin Trials. 2003;24(2):182–99.
Migraine chronification
Scher AI, Stewart WF, Buse D, Krantz DS, Lipton RB.
Major life changes before and after the onset of chronic
174
daily headache: a population-based study. Cephalalgia.
2008;28(8):868–76.
Scher AI, Stewart WF, Ricci JA, Lipton RB. Factors
associated with the onset and remission of chronic daily
headache in a population-based study. Pain.
2003;106(1–2):81–9.
Schulman E, Levin M, Lake AE, Loder E, eds. Refractory
Migraine. New York, NY, Oxford University Press,
2010.
Medication agreements
Arnold RM, Han PK, Seltzer D. Opioid contracts in chronic
nonmalignant pain management: objectives and
uncertainties. Am J Med. 2006;119(4):292–6.
Saper JR, Lake AE. Borderline personality disorder and the
chronic headache patient: review and management
recommendations. Headache. 2002;42:663–74.
Saper JR, Lake AE 3rd, Bain PA, et al. A practice guide for
continuous opioid therapy for refractory daily headache:
patient selection, physician requirements, and treatment
monitoring. Headache. 2010;50(7):1175–93.
 Chapter
Medicolegal pitfalls in headache
11 management
The legal aspects of caring for patients, and fear of
malpractice suits or other legal entanglements, are
understandably matters of great concern for all physi-
cians. This chapter reviews topics of relevance to legal
aspects of headache management, including areas of
actual and potential malpractice liability. Several fea-
tures of headache influence the type of legal issues
that may arise and their likelihood. Although most
chronic headache disorders are not life threatening,
some secondary causes of headache are. In certain
types of headache, such as cluster headache, the inten-
sity of the pain makes medical treatment imperative,
not optional, for almost all patients and creates a
degree of desperation seen in few other pain disorders.
In unusual headache conditions, diagnosis and appro-
priate treatment may be delayed. Current treatments
for most primary headache disorders are not curative,
and not always effective, increasing the chance that
patients will seek disability status or require off-label,
experimental, or nonvalidated therapy. In addition,
there are serious risks associated with certain headache
treatments.
One legal area that is almost certain to involve
the headache practitioner is that of disability deter-
mination. Headache practitioners frequently receive
patient requests for information to claims for disability
payments through Social Security Disability Insurance
(SSDI) or other programs.
There is much confusion about this topic and
almost no formal training is given to medical care
providers about disability determination. Disability is
essentially a legal, not a medical, concept. It is defined
differently depending on the rules that apply in a par-
ticular situation. These range from Social Security dis-
ability rules, Workers’ Compensation laws, the Family
and Medical Leave Act (FMLA), Veterans Association
guidelines, to requirements of private insurance poli-
cies. Table 11.1 lists some common disability benefit
programs that require medical support of claims.
Medical leave and disability
determination: when to make the call?
Case
A 45-year-old information systems technician for a
large company presented for an initial visit with a past
history of clearly documented migraine without aura
that had, over the past two years, evolved to chronic
migraine. He had struggled to remain at work over the
past 18 months, using the majority of his sick time as
well as some of his vacation time to rest. His supervi-
sor had discussed the possibility that the FMLA might
cover his absences. Box 11.1 outlines the key features
of the FMLA. The patient asked the physician to fill
out paperwork to help him qualify for FMLA protec-
tion. He also asked whether the physician would sup-
port him if he decided to apply for SSDI payments.
Congress enacted FMLA in order to protect work-
ers who are ill or who have caregiving responsibili-
ties for children or other family members and need to
take time away from work for these reasons. The law
applies only to employers, including state agencies and
schools, with 50 or more workers. Employees are eligi-
ble for up to 12 weeks of unpaid FMLA leave in any cal-
endar year if they have been employed for 12 months
out of the preceding 7 years, worked at least 1250 hours
during those 12 months, and worked at or near a loca-
tion with at least 50 employees.
The FMLA law allows employers to require physi-
cian certification of a serious medical condition, and
recertification every six months for a chronic ongoing
medical problem. FMLA requires that covered work-
ers are entitled to return to their job or an equiva-
lent job when they return from leave and that they are
entitled to maintain health insurance coverage while
they are on leave. One useful feature of FMLA is that
employees are allowed to take small amounts of leave
time, for example a single day at a time, and on an
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 Chapter 11: Medicolegal pitfalls in headache management

Table 11.1. Some benefit programs that require medical provider support for claims
Funding
Program agency Jurisdiction Beneficiaries Benefits Restrictions Comments
Social Security Social Security Federal Employees; 7.7 Wage Long-term Prior work history,
Disability Tax million (2009) replacement permanent waiting period
Insurance disabled workers and medical care disability only
(SSDI)
Workers’ Employer Tax Individual Employees; 126 Wage Work-related illness In force from day one
Compensation states million (2002) replacement or injury only (limited liability for
disabled workers and medical care employer in return)
Family Medical US Dept of Federal Employees of at least 12 weeks unpaid Employer must Job is protected
and Leave Act Labor one year leave per year for have 50 or more
(FMLA) specific reasons employees
Private Private Private, may Employees injured in Wage May offset the Does not compete
Insurance be mandatory the workplace. replacement amount received with workers’
or optional to Temporary disability and medical care from Social Security compensation
employees programs protect coverage
employees, owners,
and professionals for
injury or illness at or
away from the
workplace
Veterans Veterans Federal Veterans; 3.1 million Compensation Honorable
Administration Administration claimants (2009) only discharge or left the
Disability budget service under less
than “dishonorable”
terms.

intermittent basis. Some patients may use FMLA leave
to attend office visits related to their medical condition,
for example.
Among other things, FMLA leave can be granted
for employees who have a serious health condition that
makes them unable to perform the functions of their
job, or if they need to care for a spouse, child, or par-
ent with a serious health condition. If the health con-
dition requiring FMLA leave is “foreseeable” (e.g. an
elective surgical procedure) an employee must give 30
days’ notice of the leave. For unforeseeable events, only
“practicable” notice is required.
In this case, the physician explained that he was
happy to support the patient’s request for FMLA pro-
tection so that the patient could attend office visits and
remain at his job despite headache-related absences. In
response to the patient’s request for SSDI, however, his
opinion on this first visit was that the patient’s con-
dition had not yet been aggressively treated and he
expected the patient would improve with such treat-
ment. Thus, he did not feel that he could support an
application for SSDI. The remainder of the visit was
devoted to a discussion of the proposed management.
Two weeks later the physician received a letter from
a lawyer requesting a statement of disability for this
patient.
Did the physician respond appropriately to
this patient’s request for disability?
A request for support of a disability application need
not always be met with a “yes” or “no” answer. If a
review of the patient’s medical information fails to sup-
port a decision one way or the other, then a brief note
to that effect is appropriate. In this situation, the physi-
cian has seen the patient only once and thinks it is
likely that he will improve with treatment. He is not
in a position to reach a firm conclusion about disabil-
ity and may simply note that the patient remains under
care. Thus, the physician’s response to this patient’s dis-
ability request seems appropriate.
Discussion
Physicians who treat patients with serious headache
disorders should be familiar with the provisions of
FMLA. It is a very useful way for patients to remain
employed despite severe headaches and also makes it

176
 Chapter 11: Medicolegal pitfalls in headache management
Box 11.1. Medical certification for the Family and
Medical Leave Act (FMLA)
Provides: Unpaid, job-protected leave, up to 12 work-
weeks in a 12-month period for a number of reasons,
including a serious health condition that makes the
employee unable to perform the essential functions of
his or her job. Pertinent to migraine, employees may at
times take intermittent leave.
Medical certification for a serious health condition:
The employer may require complete and sufficient cer-
tification in support of the leave from a healthcare
provider. The employee is responsible for paying for
the cost of the medical certification and for making
sure the certification is provided to the employer. The
employer may not request additional information but
may ask the provider for clarification. The employer
may also request a recertification periodically and may
request a fitness-for-duty certification when the leave
is complete.
Requested information:
r Medical facts about the condition
r Indication that the employee cannot perform the
essential functions of the job
r Estimated frequency and duration of expected
incapacity
Optional forms (e.g. WH-380-E) can be downloaded
for use in documentation of an employee’s serious
health condition.
Adapted from US Dept of Labor website: http://www.
dol.gov/whd/fmla/
possible for patients to take time off to receive needed
treatment. With regard to disability determination,
most requests for physician information will request
a determination of patient impairment and functional
capacity. Box 11.2 lists information that is commonly
needed to fill out these requests. Physicians may wish
to maintain a template in the medical record to facili-
tate collection of information about functional capac-
ity and objective findings likely to be of interest to
the disability examiner. Providers who routinely doc-
ument this information may often simply submit their
clinical notes in support of a patient’s disability claim.
Diagnosis
Chronic migraine with possible disability.
Box 11.2. Functional capacity information needed
for disability determination
Diagnosis, symptoms, physical findings, and test
results leading to disability (include all physical
findings):
Will/Has disability or impairment last/lasted one year
or more?
Does the disability or impairment prevent the patient
from standing/sitting for six to eight hours? Yes/No
If yes, what is the reason?
Does the disability or impairment require the patient
to lie down during the day?
Estimate the part-time or reduced work schedule the
employee needs, if any:
⬍⬎ hour(s) per day; ⬍⬎ days per week from ⬍⬎
through ⬍⬎.
Will the condition cause episodic flare-ups peri-
odically preventing the employee from performing
his/her job functions? Yes/No.
Is it medically necessary for the employee to be absent
from work during the flare-ups? Yes/No
If so, explain:
Estimate the frequency of flare-ups and the duration
of related incapacity that the patient may have over
the next six months (e.g. one episode every three
months lasting one to two days):
Frequency: ⬍⬎ times per ⬍⬎ week(s)/month(s)
Duration: ⬍⬎ hours or ⬍⬎ day(s) per episode.
Describe any other restrictions (what the patient is
advised not to do) or limitations (what the patient can-
not do), e.g. reaching and fine motor movements:
Tip
The Family and Medical Leave Act provides useful
job protection for workers with serious health condi-
tions such as chronic headache. Physicians should not
feel pressured to make disability determinations in the
absence of sufficient information.
Is the patient really disabled?
Case
A 32-year-old diesel mechanic presented for evalua-
tion of headache after an injury. There was no past
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 Chapter 11: Medicolegal pitfalls in headache management
or family history of migraine and no history of prior
injury. He reported that he slipped in the shop while
working and struck his right temple, with a result-
ing laceration requiring medical attention but with
no loss of consciousness. The next day he reported
headache, nausea, photophobia, and tinnitus. He was
diagnosed, by another physician, with a concussion
and treated with simple analgesic medications. An
MRI of the brain was normal. Headache and tin-
nitus were exacerbated by noise exposure at work
and the patient said he had been unable to return
to work because of the noisy work environment. A
neurologist added gabapentin and metoclopramide
and referred the patient to an otolaryngologist, who
found no abnormalities on examination. The patient
was advised to wear earplugs to limit exposure to
noise at work but he objected to this solution on the
grounds that this would interfere with his personal
safety.
When evaluated in the headache clinic four months
after the injury, symptoms had improved but he con-
tinued to report episodic disabling headaches that
occurred three to five times per week. He had not
returned to work and had an open worker’s compen-
sation case. His work history and level of activity were
not documented in detail, however, since the headache
specialist felt that his post-traumatic headaches were
likely to improve and expected that he would ulti-
mately return to work.
Further improvement was noted at a follow-up visit
several months later. The patient had begun to take
some college courses and was generally more active.
Despite this, he had not returned to work. He had
refused an offer of a job modification designed to pro-
tect him from noise at work because it was associated
with reduced pay. He also noted other problems, such
as a long commute, that he felt prevented a return to
work.
After this follow-up visit, his physician received a
request from the workman’s compensation insurer for
written certification of disability.
How should the physician respond to this
request for a determination of disability?
The patient’s employer has attempted to accommo-
date this patient’s disability. The patient has rejected
the proposed accommodations and has additional rea-
sons not to return to work. However, he is taking col-
178
lege courses and his headaches are improving. The
medical record documents this improvement in pain
and function. The most reasonable course of action
for the physician in this case is to advise the patient
that there is no clear medical reason to avoid return-
ing to work. Although uncomfortable, such a conver-
sation and approach is preferable to either ignoring
the disability request altogether or acquiescing to the
request to support the patient’s application for disabil-
ity compensation.
Discussion
To avoid future strain on the therapeutic relationship,
physicians should respond frankly to patients who
request disability certification that the physician feels
is not warranted. Any disability determination by a
physician should reflect the facts and be able to with-
stand close scrutiny in a legal system that is adversarial
by design.
Diagnosis
Post-traumatic headache with unusual and persistent
symptoms.
Tip
A seemingly routine return-to-work situation can
quickly become complicated and leave the unwary
provider awash in a swirl of legal and ethical ques-
tions. Prior training and preparation are key to han-
dling these situations effectively.
Shouldn’t someone help?
Case
A 44-year-old female was evaluated for refractory
chronic migraine present since childhood and unas-
sociated with psychiatric comorbidities. “I’ve had
headache as long as I can remember. Over the years
I’ve had multiple treatments and nothing has ever
worked.” She had been followed in several different
university clinic settings and had been compliant with
multiple different therapies but could not recall any
sustained period of headache control.
Further progression of headache had been noted
in the months before the current evaluation, with
 Chapter 11: Medicolegal pitfalls in headache management
worsening of baseline headache and superimposed
episodes of more severe pain that could last days at a
time. She was an unemployed nurse and was receiv-
ing some unemployment compensation but had never
considered or applied for disability payments.
After almost six months of intensive outpatient
management, the patient was unimproved. She had
moved back in with her mother because she was
unable to afford rent and reported that she was receiv-
ing no outside financial support of any kind. Despite
her symptoms, she was looking for work in order
to be able to pay for her private health insurance
plan.
Should this patient be advised to
seek disability?
Often the tone of disability discussions reflects sus-
picion of a patient’s motives. On occasion, however,
physicians encounter patients who are too reluctant to
seek disability status. The patient in this case seems
never to have been aware of or considered outside help,
but could benefit from it, especially if by receiving
assistance she is able to maintain her health insurance
coverage. In this setting, the provider could advise the
patient of the availability of assistance programs and
provide a referral if necessary, for example to social ser-
vices, to further guide the patient.
Discussion
Most headache experts would agree that a portion
of their patient population is disabled, some perma-
nently so. In fact, many studies of migraine-related
disability suggest that the disability associated with
chronic headache disorders such as migraine is under-
reported and underestimated. Measures of medi-
cally determined disability may not, however, always
meet legal or administrative standards for disabil-
ity determination. From a legal perspective, disability
determination usually is based upon objective med-
ical findings. Since migraine is not typically asso-
ciated with objective findings, the physician’s opin-
ion as to the basis of disability becomes especially
important.
Diagnosis
Chronic migraine.
Tip
Physicians are an important resource for disabled
patients who may be unaware of available forms of
financial assistance.
A patient who asks to record his
office visit
Case
A 70-year-old retired psychologist presented alone for
evaluation of headache. Without any discussion he
produced a tape recorder and said he wished to record
the interview because he had memory problems that
make it difficult for him to remember what doctors
tell him. He was a vague and tangential historian who
lived alone and reported a pattern of headache that
was consistent with chronic tension-type headache. He
also had many other somatic complaints. He was a fre-
quent user of medical services and had several comor-
bid conditions, including anxiety. Other providers had
indicated in their records that they allowed the patient
to tape record medical visits.
Is the request to record the visit reasonable
and should it be allowed?
Although mildly unsettling, under most circum-
stances such a practice is probably benign, and in this
case the physician allowed it. He viewed it as sim-
ilar to situations in which other patients took writ-
ten notes during a visit, or an accompanying family
member typed on a laptop during a visit. These activ-
ities usually take place without specific advance per-
mission and generally represent a desire to make sure
that medical information and recommendations are
understood and available for reference. If the patient’s
intention is simply to aid recall of the visit the activity
is probably benign and might even be useful. Advan-
tages of recording could include retention and re-
inforcement of complex information and recommen-
dations as well as reassurance for concerned family
members who could not attend the visit.
Although likely to be a reasonable request in this
situation, it is understandable that similar requests by
other patients and under other circumstances might
provoke anxiety in medical providers. The ubiquity of
smartphones and other devices makes recording visits
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 Chapter 11: Medicolegal pitfalls in headache management
easy to do, and such requests are likely to become more
common in the future.
What are the potential pitfalls or harms
associated with recording of medical visits?
Potential pitfalls associated with tape recordings of
medical visits include the possible compromise of pri-
vacy. Even if they instigated the taping, patients might
be concerned that others in their family will gain
access to the tapes, and be more guarded in the his-
tory they provide to the physician. Similarly, physi-
cians concerned about the future use of the tape, or
about the possibility that remarks might be taken out
of context, may become more guarded in their dis-
cussion and take a more defensive attitude towards
treatment.
In this case, the patient requested permission to
record a visit, but surreptitious recording is certainly
possible. If this comes to light later on, physicians
might understandably feel that the behavior indicates
a lack of trust in his or her recommendations or worry
that the patient is litigious. Although records of med-
ical conversations are generally considered to be pro-
tected health information, if the material is under the
voluntary control of the patient typical legal restric-
tions do not apply. Patients are free to share their health
information with whomever they wish; it is medical
providers and healthcare entities that are subject to pri-
vacy rules.
If providers feel uncomfortable about a patient
request to record a medical visit, there are several pos-
sible courses of action. The request could be denied
and the patient told that the practice seems intrusive
and will limit opportunities for a frank discussion. If
the request is refused, it may be prudent to inquire
about the reason for the request, since this might be
addressed in other ways. It could be, for example, that
a patient seeking to record a visit would be satisfied
with a more detailed set of written recommendations,
a copy of the finished visit note, or a call by the physi-
cian to a concerned spouse to explain things the patient
feels he or she will not be able to recall. As part of this
discussion it may be helpful for the provider to state
what he or she suggests be done to improve the prob-
lem while not necessarily simply agreeing to a patient’s
request, for example by saying “I’m sorry I can’t
allow — but am happy to — instead.”
180
Discussion
Since it seems likely that technologic advances will
increase the frequency of patient requests to record
medical visits, physicians may want to institute policies
about the use of various technologies during the office
visit. If recording will not be allowed, it is prudent to
consider giving notice of this policy, for example a sign
in the waiting room might indicate, “no audio or video
recording is allowed in this office.”
Diagnosis
Chronic tension-type headache.
Tip
Discussion about office policies about audio or video-
taping of medical visits can help prevent confusion and
delay when such requests arise.
Overreliance on steroids in
cluster headache
Case
A 43-year-old man described a 23-year history of
90-minute daily or twice-daily headaches that met cri-
teria for cluster headache. The headaches were uni-
lateral, behind his left eye, and associated with ipsi-
lateral nasal stuffiness and ptosis. For many years the
patient experienced only one or two bouts of cluster
headache a year, often in the spring and fall. These
periods of headache susceptibility would typically last
two months, during which headache attacks occurred
one to several times a day. During cluster bouts the
patient managed individual headaches with sumatrip-
tan. After two months headaches would remit and he
was completely headache-free until the next bout.
Three years ago he developed chronic cluster
headache and his new insurance company would not
provide him with sufficient sumatriptan to treat all of
his attacks. Preventive treatment with verapamil at a
dose of 80 mg twice daily was ineffective. He was then
placed on prednisone 60 mg a day and reported he only
had headaches “when I forget to take it or some fool
doctor tries to take me off.” He was in good health but
had a hip replacement last year because of osteonecro-
sis of the hip. He was told this was probably caused
by his steroid treatment, but responded, “if steroids
 Chapter 11: Medicolegal pitfalls in headache management
are the only thing that works, what am I supposed to
do?” The patient was on 60 mg of prednisone a day and
asked to have the prescription refilled.
What is the role of corticosteroids in the
treatment of cluster headache?
In our practice we think of cluster headache (some-
times known as “suicide headache”) as a true headache
emergency. Most patients, like the one described here,
are desperate for rapid, reliable relief from the agoniz-
ing, unpredictable attacks. Injectable sumatriptan or
oxygen is typically effective for treatment of individ-
ual headaches, but relying solely on symptomatic treat-
ment of attacks is impractical and forces patients to
endure short periods of intense pain while waiting for
treatment to take effect. Thus, most cluster headache
patients should be offered daily preventive medicine,
which is given with the aim of reducing or eliminating
the headaches.
A short course of oral corticosteroid treatment –
often referred to as “bridging therapy” – can suppress
cluster headaches during the week or so it may take
preventive treatment to become effective. Patients usu-
ally are grateful to find that steroids work quickly, and
steroids may seem to have few side effects, at least ini-
tially. The mild euphoria steroids produce also may
relieve the dread associated with severe, unpredictable
episodes of pain.
Unfortunately, repeated or long-term treatment
with corticosteroids can cause serious side effects such
as osteonecrosis of the hip. Occasionally even relatively
short courses or low doses of steroids can produce seri-
ous problems. Most doctors in a headache specialty
practice have seen patients like this who are steroid
dependent and have suffered serious medical conse-
quences as a result.
How can steroid dependence and
complications be avoided?
The use of corticosteroids to treat cluster headache,
though off-label, cannot be completely avoided, but
the drugs should be used with caution, in the small-
est doses for the shortest period of time neces-
sary to allow a transition to other, safer treatments.
The mainstays of preventive treatment for cluster
headache are verapamil and lithium, either alone or in
combination.
The dose of verapamil necessary to control clus-
ter headache may be very high, and heart block or
constipation pose important safety and tolerability
problems. These problems are reversible, however, and
can often be prevented or caught early with care-
ful monitoring. Lithium is perceived to be highly
effective for chronic cluster headache, but patients
may prefer to avoid a drug they associate with bipo-
lar disorder. Blood tests and electrocardiograms are
needed to monitor treatment and can be inconve-
nient. For the patient described in this case, attacks
finally came under control on a preventive regimen
of 240 mg of sustained release verapamil twice daily,
along with 300 mg of lithium carbonate three times
daily. He was slowly weaned from steroids over several
months.
Discussion
The off-label use of steroids for cluster headache has
not been carefully studied, owing to the rarity of the
disorder. Many patients, however, report that steroids
help temporarily but over the long run seem to make
headaches worse. Some even suspect that steroid treat-
ment may prolong bouts of cluster headache. Many
seasoned cluster headache veterans believe that the
short-term benefits of steroid treatment are not worth
the problems they can cause when used repeatedly over
many bouts of cluster headache.
A frank discussion with patients prior to any pre-
scription of corticosteroids is important, and it may
be appropriate to provide written information about
potential side effects and harms. It is not uncommon
for patients who have suffered serious steroid-related
complications from cluster headache treatment to say
that they were not warned about side effects when
the drugs were prescribed. In one review of medico-
legal aspects of cluster headache, adverse events from
steroid treatment, particularly osteonecrosis of the hip,
were identified as a cause of several large malpractice
liability payments.
There are few published guidelines or protocols to
help the clinician decide on a weaning schedule for
patients who are steroid dependent, but patients who
have become steroid dependent must be weaned from
steroids carefully to avoid precipitating adrenal insuffi-
ciency. Patients remain at risk of acute adrenal insuffi-
ciency during periods of critical illness for up to a year
after discontinuation.
181
 Chapter 11: Medicolegal pitfalls in headache management
One weaning strategy, developed for patients with
inflammatory bowel disease, is to switch patients tak-
ing prednisone to an equivalent dose of dexametha-
sone, assuming that 0.75 mg of dexamethasone is
equivalent to 5 mg of prednisone. Using 0.5 mg tablets
of dexamethasone, reductions of 0.5 mg can be made
every few weeks until the patient is off steroids.
Diagnosis
Chronic cluster headache with steroid dependence.
Tip
Short-term “bridging therapy” with oral cortico-
steroids can bring rapid relief to patients with clus-
ter headache, but repeated courses of steroid treatment
can cause serious harm and exposure of the physician
to legal risk. Corticosteroids should be used cautiously
and for short periods of time.
A request for medical marijuana to
treat migraine
Case
A 24-year-old woman with transformed migraine and
medication overuse presented for initial evaluation at
a headache clinic. Her fiancé accompanied her. The
patient met criteria for a diagnosis of chronic migraine.
She reported that she was taking amitriptyline pre-
scribed by her primary care physician but that her
symptoms were not fully controlled. She used ibupro-
fen and a triptan for individual attacks of headache
and these medications provided some relief. She had
also tried vaporized marijuana and found it very help-
ful for the headaches. In fact, she reported that it was
as effective as her triptan. She also reported that it
improved the quality of her sleep. She asked whether
the physician would provide a letter of medical neces-
sity supporting her use of medical marijuana. Vot-
ers in the state had recently approved a ballot ques-
tion that allowed patients with “debilitating medical
conditions” to obtain and use marijuana for medical
reasons. The physician declined the patient’s request
and suggested alternative combinations of standard
abortive and preventive medications. However, the
patient’s fiancé repeatedly interrupted the discussion
and insisted the physician provide a letter allowing the
patient to obtain medical marijuana.
182
What are the legal implications of
supporting a patient’s request for medical
marijuana?
Voters in many states have approved ballot questions
that allow the use of marijuana for medical purposes.
Although marijuana is a Schedule I controlled sub-
stance under US federal law and remains unavailable
by prescription, providers can write letters certifying
the medical necessity for such treatment for serious
medical conditions, including headache. Patients are
then able to purchase marijuana from approved medi-
cal marijuana dispensaries. In Massachusetts, qualify-
ing patients are allowed to possess a 60-day supply (10
ounces) of marijuana for personal use.
Although straightforward on one level, there are
potential medicolegal pitfalls for physicians who cer-
tify patients for the use of medical marijuana. In the
situation described in this case there is the additional
possibility of coercion based on the behavior of the
patient’s fiancé. It is possible that he wishes to grow
and use (or possibly distribute) marijuana under an
umbrella of legal protection provided by the physician
and in the name of the patient.
This is certainly a less well-defined situation than
is the routine prescribing of a pharmaceutical grade
medication for a patient. Determining the true inten-
tions of a patient seeking a letter supporting the use
of medical marijuana may at times be difficult or
impossible.
What advice should be given to this patient
about the harms and benefits of marijuana
in headache treatment?
Marijuana has not been carefully studied as a treat-
ment for migraine or other headache conditions, even
though descriptions of marijuana-based treatments
for headache date far back in history. In the 1850s,
for example, Sir William Osler advocated daily mar-
ijuana use as a treatment for migraine. Endogenous
cannabinoids act as neurotransmitters through a series
of receptors throughout the brain and other organs
and may produce antinociceptive and neuroprotec-
tive effects, and reduced levels of endogenous cannabi-
noids have been found in the spinal fluid of chronic
headache subjects.
Although it is plausible that medical marijuana
could be an appropriate therapy for some forms of
 Chapter 11: Medicolegal pitfalls in headache management
headache, there are as yet no guidelines as to when and
how to use this therapy in the headache patient. There
also is no high quality evidence supporting the effi-
cacy of marijuana in headache management but there
is some evidence suggesting potential harms. Mari-
juana use has been associated with the development
of reversible cerebral vasoconstrictive syndromes, and
it is possible that patients with migraine are particu-
larly susceptible to this problem. Regular use of mar-
ijuana in the migraine patient, especially in com-
bination with selective serotonin reuptake inhibitor
drugs, has been associated with the development
of the reversible cerebral vasoconstrictive syndrome
with headache worsening and focal MRI changes.
Other potential adverse effects relevant to migraine
management include mood changes and memory
dysfunction.
Discussion
Although marijuana use remains illegal under federal
law, a growing number of states* have legalized medi-
cal marijuana and physicians can expect to encounter
patients requesting medical marijuana with increas-
ing frequency. The landscape is changing rapidly but
unfortunately information is scarce about the poten-
tial associated medical and legal dangers for physicians
and patients. Careful documentation of advice given to
patients about this matter is important and likely to be
protective for all involved.
*AK, AZ, CA, CO, CT, DC, DE, HI, MA, ME, MI, MT,
NV, NJ, NM, OR, RI, VT, and WA.
Diagnosis
Chronic migraine.
Tip
The harm-to-benefit balance of marijuana as a treat-
ment for headache disorders is uncertain. In the
absence of firm evidence of benefit and given the pos-
sibility of serious adverse events related to use, physi-
cians should be cautious about certifying patients for
medical marijuana, as they would be in recommend-
ing the use of other treatments whose effects are poorly
understood.
Risks associated with prescribing
off-label medication
Case
A 35-year-old female with high frequency episodic
migraine presented for evaluation. Her neurologic
examination and vital signs were normal. After discus-
sion, she was advised to consider preventive therapy to
decrease the frequency of headaches. Because she was
planning to become pregnant, the physician recom-
mended avoiding divalproex or topiramate. Instead,
the patient was prescribed a low dose of metoprolol
with plans for a slow upward titration of the dose.
Two weeks into her treatment, the patient reportedly
became dizzy and fainted at work, sustaining a scalp
laceration that required sutures. She was advised to
stop the metoprolol.
At her next visit her husband accompanied her.
He was a lawyer, and was concerned because he had
learned that metoprolol was used to treat heart and
blood pressure problems and was not approved by
the US Food and Drug Administration (FDA) for use
in migraine. He wondered why this medication had
been prescribed in a headache clinic and why his wife
had not been informed that it was an unapproved
treatment.
Did the provider do anything wrong?
Although not every headache expert would have pre-
scribed metoprolol as first-line treatment for this par-
ticular patient, it was certainly a reasonable treatment
choice. Although the drug does not have an FDA indi-
cation for migraine treatment, it is in the same ther-
apeutic beta-blocker medication class as two other
drugs that are approved to treat migraine: propranolol
and timolol. In addition, several placebo-controlled
studies support metoprolol as an effective treatment
for migraine. On the basis of this evidence, metopro-
lol received the highest rating (Level A) in the recent
joint American Headache Society/American Associ-
ation of Neurology migraine prevention guidelines.
Many other migraine preventives recommended by
that guideline also do not have FDA approval for
migraine prevention.
Although physicians are understandably con-
cerned about the legal risks associated with pre-
scribing off-label medications, one paradox of cur-
rent practice is that most third-party payers will not
183
 Chapter 11: Medicolegal pitfalls in headache management
reimburse for treatment of chronic migraine with
onabotulinumtoxinA unless patients have previously
failed to obtain benefit from a number of other drugs.
These include many that are not FDA approved for
migraine treatment.
How can this situation best be handled?
Providers may become accustomed to prescribing
what they view as standard therapy and neglect to dis-
cuss the off-label nature of recommended treatments
with patients. Some may consider such disclosure to
be an unimportant matter. As the husband’s question
in this case makes clear, however, this view is unlikely
to be shared by patients, especially if they suffer an
adverse event related to the medication. The further a
therapy is outside the mainstream and the more poten-
tial risk involved, the more important it probably is to
fully discuss and document patient understanding and
acceptance of an off-label therapy before initiation of
treatment.
In general, informed consent requires that a patient
be provided with enough information about the bene-
fits and risks of a proposed treatment in order to make
an informed decision. Material risks that could be of
significance to the patient should be disclosed and dis-
cussed. Assent is implied if the patient accepts the plan
and voices no dissent, and currently the use of off-label
drugs in a clinical setting requires no special written
consent. It is noteworthy, however, that written con-
sent would be required of participants in a drug trial
for a new indication of an established drug because the
drug’s risks and benefits would have yet to be proved
(for the purposes of FDA approval). Whether the off-
label use of medication constitutes a separate risk over
and above risks of the same medication for an indi-
cated use is uncertain given the level of evidence sup-
porting many off-label medications for headache, but
this should be considered carefully when less is known
about a treatment. Finally, physicians should prescribe
medications only for indications that they believe are
in the best interest of the patient on the basis of the
most credible available evidence.
In this case, the physician first expressed her dis-
tress about the patient’s experience by saying “I am
sorry that this happened to you.” She then spent time
explaining her choice of medication to the patient and
her husband. The patient’s husband, who had not been
at the original visit, said that he accepted the physi-
cian’s explanation for the treatment with metoprolol,
184
and understood that although his wife’s experience
had been an exception, overall this had not been a par-
ticularly unusual or risky treatment.
Discussion
A review of off-label prescribing in migraine con-
cluded that it was not only common but an inte-
gral part of headache practice and, at least for com-
monly used drugs, within the standard of care. For
a number of headache disorders there are no FDA-
approved therapies. For example, there are no FDA-
approved preventive treatments for cluster headache,
but good quality evidence supports the use of vera-
pamil and lithium and essentially all headache physi-
cians routinely employ these medications for that pur-
pose. Similarly, there are no approved treatments for
other trigeminal autonomic cephalgias, some of which
are even defined by their response to an off-label ther-
apy (e.g. the indomethacin responsive-headache syn-
dromes). Many commonly used pediatric therapies are
off-label since relatively few medications are tested in
pediatric populations prior to marketing.
US Food and Drug Administration approval of a
medication for a specific indication implies that, when
used in accordance with label instructions, the drug
meets a minimum set of efficacy and safety standards.
The testing process to gain FDA approval for indi-
vidual indications or dosing regimens is cumbersome
and expensive. Because of this manufacturers often
choose not to obtain approval for all possible uses of
a drug. Thus, the label for any particular drug will not
list all potential medical uses, even some for which
there is good clinical trial or other evidence of effi-
cacy. This distinction between FDA approval and sci-
entific validation of a drug’s usefulness is an important
one. In recognition of this distinction the FDA notes
that “accepted medical practice includes drug use that
is not reflected in approved drug labeling” and that
“once a drug has received FDA approval for any indica-
tion, physicians may prescribe it for other conditions,
in other doses, or for different populations than those
listed in approved labeling.”
Although off-label medication use is clearly com-
mon and defensible, there is no clear definition of
what constitutes acceptable off-label medication use.
The use of metoprolol in this case seems acceptable.
Less acceptable uses might include prescribing an off-
label medicine based on only anecdotal evidence of
benefit in a patient who has not had previous trials of
 Chapter 11: Medicolegal pitfalls in headache management
standard therapy, especially if this is done without a
clear discussion about the nature of use.
Diagnosis
High frequency migraine without aura; syncope
related to medication-induced hypotension.
Tip
Minimize the legal risks of off-label drug use by pro-
viding patients with clear and relevant information
about the benefits and harms of any proposed therapy.
Further reading
Disability and the Family and Medical Leave Act
Buse DC, Manack AN, Fanning KM, et al. Chronic
migraine prevalence, disability, and sociodemographic
factors: results from the American Migraine Prevalence
and Prevention Study. Headache. 2012;52:1456–
70.
Doyle HA. Sound medical evidence: key to FECA claims.
Monthly Labor Review. September 1991, 26–28.
Holmes WF, MacGregor EA, Sawyer JP, Lipton RB.
Information about migraine disability influences
physicians’ perceptions of illness severity and treatment
needs. Headache. 2001;41:343–50.
Leonardi M, Raggi A, Ajovalasit D, et al. Functioning and
disability in migraine. Disabil Rehabil. 2010;32(S1):
S23–32.
United States Department of Labor. Leave Benefits. Family
and Medical Leave Act. http://www.dol.gov/dol/topic/
benefits-leave/fmla.htm.
Overreliance on steroids
Byyny RL. Withdrawal from glucocorticoid therapy. N Engl
J Med. 1976;295:30–2.
Loder E, Loder J. Medicolegal issues in cluster headache.
Curr Pain Headache Rep. 2004;8(2):147–56.
Murphy SJ, Wang L, Anderson LA, et al. Withdrawal of
corticosteroids in inflammatory bowel disease patients
after dependency periods ranging from 2 to 45 years: a
proposed method. Aliment Pharmacol Ther. 2009;
30:1078–86.
Weinstein RS. Glucocorticoid-induced osteoporosis and
osteonecrosis. Endocrinol Metab Clin North Am. 2012;
41(3):595–611.
Zhao FC, Li ZR, Guo KJ. Clinical analysis of osteonecrosis
of the femoral head induced by steroids. Orthop Surg.
2012;4(1):28–34.
Medical marijuana
An Act for the Humanitarian Medical Use of Marijuana.
http://www.malegislature.gov/Laws/SessionLaws/Acts/
2012/Chapter369.
Chen SP, Fuh JL, Wang SJ. Reversible cerebral
vasoconstriction syndrome: current and future
perspectives. Expert Rev Neurother. 2011;11:1265–76.
Ducros A, Boukobza M, Porcher R, et al. The clinical and
radiological spectrum of reversible cerebral
vasoconstriction syndrome. A prospective series of 67
patients. Brain. 2007;130:3091–101.
McGeeney BE. Cannabinoids and hallucinogens for
headache. Headache. 2013;53(3):447–58.
Off-label drug use in headache
Loder EW, Biondi DM. Off-label prescribing of drugs
in specialty headache practice. Headache. 2004;44:
636–41.
Mithani Z. Informed consent for off-label use of
prescription medications. Virtual Mentor. 2012;
14(7):576–81.
Wittich CM, Burkle CM, Lanier WL. Ten common
questions (and their answers) about off-label drug use.
Mayo Clin Proc. 2012;87(10):982–90.
185
 Index

Note: page numbers in italics refer to figures and tables, those in bold refer to boxes

acetaminophen pitfalls 73–83 cerebrospinal fluid (CSF), headache

oxycodone combination 167
during pregnancy 114
acupuncture 149–50
acute bacterial rhinosinusitis (ABRS)
21
acute headache
agitation after treatment 108–9
triptan treatment 102
acute retroviral syndrome 80–1
acute sphenoid sinusitis 40–1
adherence to medication 78–9, 132
agitation after treatment for acute
headache 108–9
akathisia, neuroleptic-induced 108–9
Alice in Wonderland syndrome 10–11
allergies, multiple 148–50
amitriptyline 135–6, 170–1
anticholinergic drugs 108–9
antiemetics, during pregnancy 114–15
antiepileptics, combination therapy
139
antiviral drugs 95
aspirin 32–3
atenolol, during breast-feeding 116
autonomic features, migraine 12, 13
availability bias in diagnosis 42–3,
58
behavioral therapies 148, 149
chronic migraine 167
people benefitting 150
preventive 129–30
response to 150
benzodiazepines 108–9
beta-blockers
combination therapy 139
in pregnancy 129
side effects 134
blood pressure 127
see also hypotension
blood tests
iatrogenic harm and migraine 81–3
lithium use 78–9
menstrual headache hormone
testing 73–5
nonadherence to therapy 78–9
verapamil monitoring in cluster
headache 75–6
body aches, rash, and headache 80–1
bone loss, topiramate side effect 136–7
Borrelia burgdorferi 24
Botox 139–41
brainstem aura, migraine 35, 35
breast-feeding
episodic migraine 115–17
headache treatment 115–17
medication safety 116, 115–16, 117
bruxism 25
butalbital
hemiplegic migraine treatment
96
medication agreement 172
medication overuse headache 170–1
post-ictal headache 44
during pregnancy 114
butterbur 151
CADASIL 63, 97
molecular genetic testing 63–4
white matter lesion familial
occurrence 62–4
carbon monoxide intoxication
management 43
weekend headache 41–3
cardiovascular events, NSAID adverse
effects 107, 108
cardiovascular investigations, for
triptan sensations 102–3
carotid artery dissection 154
with Horner’s syndrome 93–5
carotid cavernous fistula 45–6
cerebellar tonsils, low-lying 27–30
descent
crowding of posterior fossa
moderate 28
treatment for headache 29
cerebral autosomal dominant
arteriopathy with
subcortical infarcts and
leukoencephalopathy see
CADASIL
cerebral venous thrombosis 51, 50–2
with neurologic deficit and
lymphocytosis 90
cerebrospinal fluid (CSF) pressure, low
68–70
cervicogenic headache 68, 152–3
chiropractic care 153–5
diagnosis 153
Chiari 1 malformation (CM1) 28, 28–9
headache 29
MRI features 28, 29–30
Chiari malformations, classification 30
children, Alice in Wonderland
syndrome 10
chiropractic care 150, 153–5
chronic headache
continuous 15–17
differential diagnosis 15
risk factors for development 120
chronic renal failure, mild 107–8
cluster headache
dental problem 30–1
diagnosis 9–10, 12
drug treatment 155–6
episodic 30–1, 112–13
features 75–6
gender 8–10, 30, 156
intermittent red eye with headache
45
lithium
monitoring 78–9
treatment 181
migraine differential diagnosis 9, 13
occipital nerve block 156
oxygen therapy 113, 113, 155–6, 157
pregnancy 155–7
preventive treatment 9, 76
severe episodic headache in woman
8–10
steroid overreliance 180–2
steroid treatment role 181
sumatriptan limited access 112–13
timing 155
treatment monitoring 73
unilateral 7–8
verapamil monitoring 75–6
coenzyme Q10 (CoQ10) 150–2

186

combination therapy
preventive treatment 126, 126, 127,
138–9
avoidance 139
seizures 137–8
triptans 102
verapamil with propranolol 138–9
complementary therapies 148–50
computed tomography (CT)
conditions missed 69
for migraine 55
radiation risks 55, 82
contraception, topiramate effects 137
cough headache 28, 28–9
craniosacral therapy 150
defensive medicine 58
dental problem, cluster headache
30–1
dexamethasone, status migrainosus
111–12
diagnostic testing, pitfalls
dietary triggers 145–7
dihydroergotamine (DHE) 133
protocol 111, 111
disability determination 175–8
chronic migraine 175–9
functional capacity information 177
physician response 176
post-traumatic headache 177–8
process 176–7
refusal 178
reluctance to seek 179
divalproex 129
droperidol 111, 111
dystonia, neuroleptic-induced 108–9
elderly people
blurry vision on amitriptyline 135–6
focal headache 95–6
focal neurologic deficit 31–3
giant cell arteritis and persistent
headache on steroids 92–3
new headache in elderly woman
38–40
seizure with tension-type headache
treatment 137–8
electrocardiography (ECG)
abnormalities with verapamil
treatment 75
eletriptan 170–1
elimination diets 146–7
emotional stress 3
encephalitis, diagnosis 90–1
environmental toxins 42–3
epidural blood patch 64–5
epilepsy
post-ictal headache 43
see also seizures
ethinyl estradiol, topiramate
interaction 137
extra-pyramidal side effects of
neuroleptic drugs 108–9
eye
intermittent red eye with headache
45
medication-induced adverse events
135–6
subtle findings 93–5
falls, with migraine treatment 133–5
Family Medical Leave Act (FMLA)
176, 175–7
medical certification 177
fasting, migraine trigger 146
fatigue with drug-induced hypotension
138–9
fentanyl 76–8
fever and nausea with headache 40–1
feverfew 151
focal headache in older woman 95–6
focal neurologic deficit 31–3
Food and Drug Administration (FDA),
approved treatments 184
foramen ovale see patent foramen
ovale
funduscopy, medulloblastoma 46, 47
gastric bypass surgery 100, 101, 167
gender
cluster headache 8–10, 30, 156
migraine occurrence 7–8
giant cell arteritis
new headache in elderly woman
38–40
persistent headache on steroids in
elderly woman 92–3
steroid treatment 40
temporal artery biopsy 39, 40
visual loss 39
ginger 151
glaucoma, acute angle-closure 45
older woman on amitriptyline
135–6
topiramate-induced 135
Haemophilus influenzae septicemia 40
head trauma 141–3
headache diary 4, 3–4, 162
calendar 164
compliance 163
information overload 163
menstrual headache 74–5
patient recall comparison 163
headache with neurologic deficit and
CSF lymphocytosis (HaNDL)
90–2
hemicrania continua 17–18
Index
hemiplegic migraine 96–8
herbal supplements
migraine 151, 151–2
preventive 130
safety issues 152
herpes simplex encephalitis 65–6
herpes zoster 95–6
hip osteonecrosis, steroid
therapy-induced 180–1
history taking 84
abuse 88–9
carotid dissection with Horner’s
syndrome 93–5
divergent outcomes 87–8
focal headache in older woman
95–6
giant cell arteritis and persistent
headache on steroids in elderly
woman 92–3
headache with neurologic deficit and
CSF lymphocytosis 90–2
neurologic deficit 90–2
premature closure 94
psychiatric illness with intractable
headache 88–90
trauma 88–9
weakness and headache 96–8
HIV infection 80–1
Horner’s syndrome, with carotid
dissection 93–5
hydrocodone 167
hypertension, headache association
127
hypotension
drug-induced and fatigue 138–9
orthostatic 133–5
ibuprofen
adverse effects 106–7
during breast-feeding 116
imaging
CADASIL 62–3
ethics 58
headache with neurologic deficit and
lymphocytosis 90
HIV infection 81
low CSF pressure headache 70,
70
migraine 55–7
pitfalls 54–64
post-dural puncture headache 64
reversible vasoconstrictive
syndrome 60
side-locked headache 93
thunderclap headache 59–61
white matter lesions
familial occurrence 63
in migraineur 61, 62
worst headache ever 87
187
 Index
immunosuppression, secondary
headache 80–1
indomethacin 14, 18
informed consent 184
intracranial hypotension, spontaneous
69, 68–9, 70
laboratory testing
accuracy 82
focal headache in older woman
95
multiple abnormalities with
headache 81–3
pitfalls 73–83
predictive value 82
sensitivity/specificity 81–2
treatment monitoring 73
lactation see breast-feeding
legal issues see medicolegal pitfalls
lisinopril 133–5
lithium
blood tests 78–9
cluster headache treatment 78–9,
181
side effects 79
low CSF pressure headache 68–70
MRI features 70, 70
lumbar puncture (LP)
anatomy 67
guidelines 68
headache following 64–5
herpes simplex encephalitis 65–6
indications 65–6
optimizing performance 66–8
pitfalls 64–70
procedure 67–8
risk factors for headache 66
spontaneous intracranial
hypotension 68–70
worst headache ever 87
Lyme disease 23–5
deer tick 24
headache incidence 23
neuroborreliosis symptoms 24
symptoms 24, 24
magnesium supplements 150–1
malignant hypertension 127
management challenges 162–73
lifelong refractory migraine 162–3
medication agreements 172–3
medication overuse headache
early refill requests 167–9
recurrent 170–2
opioid use request 169–70
suboptimal outcomes 165
unrealistic expectations 164–6
warning signs 171
management errors 100–17
188
agitation after treatment for acute
headache 108–9
chest pressure from sumatriptan
102–4
headache treatment during lactation
115–17
migraine during pregnancy 114–15
migraine failure to respond to
triptans 100–2
NSAID-induced gastritis 106–8
serotonin syndrome 104–5
status migrainosus 111–12
sulfa allergy with migraine 105–6
vomiting with intractable headache
109–11
manual therapies 153
marijuana prescribing 182–3
maxillary sinus, mucosal thickening 21
medical cascade 82, 83
medication agreements 173, 172–3
medication overuse headache 23–5,
121
acute treatment with low risk 169
with chronic migraine 132–3
early refill requests 167–9
handling of requests for medication
168
management optimization 172–3
medication agreement 172–3
medication use limits 168, 169
migraine chronification 167
realism of treatment goals 167–8
recurrent 170–2
team approach 171–2
types 171
warning signals 171
medication use limits 168, 169
medications, off-label prescribing
183–5
medicolegal pitfalls 175–85
disability determination 175–8
chronic migraine 175–9
post-traumatic headache 177–8
marijuana prescribing 182–3
off-label prescribing 183–5
recording of medical visits 179–80
steroid overreliance in cluster
headache 180–2
medulloblastoma 46–7
MELAS (mitochondrial myopathy,
encephalopathy, lactic acidosis,
and stroke-like symptoms) 63,
97
meningitis, diagnosis 90–1
menstrual headache
hormone testing 73–5
serotonin syndrome 104–5
meprobamate 76–7
metamorphopsia 10, 11
metoclopramide 111, 114
metoprolol 183, 184–5
migraine
acute sphenoid sinusitis differential
diagnosis 41
aggravating factors 148
with aura
Alice in Wonderland syndrome 11
diagnosis 6–7
differential diagnosis 85
differential diagnosis for
prolonged aura 33–4
estrogen-containing oral
contraceptive contraindication
6
incidental white matter lesions
61–2
management 97
migrainous infarction 49–50
patent foramen ovale testing
157–8
pregnancy complications risk 129
prolonged 33–4
stabbing headache 13–15
stroke risk 6
symptoms 5–6
visual aura with sore head 85, 86
without aura differential
diagnosis 5–7
autonomic features 12, 13
availability bias in diagnosis 42–3, 58
basilar 35
with brainstem aura 35, 35
change in pattern 65–6
chronic 26
botulinum toxin use 139–41
case 57
with cerebellar tonsillar ectopia
30
disability determination 175–7,
178–9
early refill requests 167–9
imaging 57–9
lifelong 162–3
medication agreement 172–3
medication follow-up 167
medication overuse headache
132–3
opioid use request 169–70
with parasthesias 131–2
prevention of transition 166
refractory 124–7
reluctance to seek assistance 179
surgery 159–60
transformation to 86–8, 121–3,
166–7
unrealistic expectations 164–6
chronification 86–8, 121–3
medication overuse 167

patient lost to follow-up 166–7
prevention 166
risk factors 166
cluster 11–13
cluster headache differential
diagnosis 9, 13
crash 59
diagnostic accuracy 3–4
diagnostic criteria 1–2
dietary triggers 145–7
episodic 43
during breast-feeding 115–17
dietary triggers 145–7
high frequency 119–24, 166,
183–5
natural treatments 150–2
preconception planning 128–30
preventive treatment 122, 119–22,
124
with sulfa allergy 105–6
family history 142
fatal 49–50
gender 7–8
hemiplegic 96–8
herbal treatment 151, 151–2
history taking 1–2
iatrogenic harm 81–3
imaging 55–7
chronic 57–9
incidental findings 56
medical reasons 56, 57
patient reassurance 56, 57
incidence 82
intractable with vomiting 109–11
late-life 32, 32, 33
with low-grade astrocytoma 57–9
marijuana prescribing 182–3
medication side effects sensitivity
134–5
menstrual 73–5, 104–5
misdiagnosis 8
natural treatments 150–2
neurologic deficit 97
nonpharmacologic treatment
148–50
nutritional supplements 151,
150–2
orthostatic syncope 133–5
patient recall 162–3
postpartum headache 27
pregnancy 114–15
planning 147–8
principles of prevention 125
progression 47, 48
refractory 54–5, 124–7
lifelong 162–3
opioid use request 169–70
rhinosinusitis 22–3
seizure relationship 44
Index
sleep-disordered breathing 47 neurologic deficit
snoring 47 focal 31–3
status migrainosus 111–12 history taking 90–2
tension-type headache differential migraine 97
diagnosis 4, 1–4, 5 patent foramen ovale testing in
topiramate long-term safety 136–7 migraine with aura 157–8
triggers 3, 147–8 neurotoxins 140
avoidance 148 new daily persistent headache (NDPH)
dietary 145–7 15–17
triptan therapy 9, 29 clinical characteristics 15
failure to respond 100–2 clinical features 16
unilateral severe headache 7–8, diagnosis 16, 17
17 diagnostic criteria 15
with vertigo 34–6 epidemiology 16–17
diagnostic criteria 36 onset 16–17
vestibular 35 pathophysiology 16
vitamin supplements 151, 150–2 secondary causes 16
weekend headache differential treatment 16
diagnosis 42 new headache in elderly woman
weight gain 123–4 38–40
when to consider prevention 119 new headache with nausea and fever
without aura 5 40–1
with aura differential diagnosis nonpharmacologic treatment 145–60
5–7 acupuncture 149–50
chest pressure from sumatriptan behavioral therapies 148, 149
102–4 people benefitting 150
Chiari malformation 1 differential preventive 129–30
diagnosis 29 cervicogenic headache 152–3
diagnosis 2, 3, 12–13 chiropractic care 150
high frequency 183–5 tension-type headache and
transformation to chronic cervicogenic headache 153–5
migraine 86–8 cluster headaches in pregnancy
migraine deactivation surgery (MDS) 155–7
159, 160 complementary therapies 148,
migraine surgery 159–60 149–50
migrainous infarction 49–50 dietary triggers for episodic
migralepsy 44 migraine 145–7
mitochondrial myopathy, herbal supplements
encephalopathy, lactic acidosis, migraine 151, 151–2
and stroke-like symptoms preventive 130
(MELAS) 63, 97 safety issues 152
morning headache migraine and pregnancy planning
medulloblastoma 46–7 147–8
obstructive sleep apnea 47–8 migraine surgery 159–60
mixed tension-type and migraine
naproxen, adverse effects 107 headaches 148–50
nasal cavity disorders 22 multiple allergies 148–50
nasal mucosa/nasal septum disorder neck and head pain 152–3
22 nutritional supplements
natural treatments migraine 151, 150–2
migraine 150–2 preventive 130
see also complementary therapies; patent foramen ovale testing in
herbal supplements; migraine with aura 157–8
nutritional supplements response to 150
nausea and fever with headache 40–1 spinal manipulation 149, 154
neck and head pain 152–3 therapies 149
neck pain 3 triggers 147–8
neuroleptic drugs, extra-pyramidal vitamin supplements, migraine 151,
side effects 108–9 151–2
189
 Index
nonsteroidal anti-inflammatory drugs
(NSAIDs)
adverse effects 106–8, 121
gastric ulceration side effects 101,
121
triptan combination therapy
102
norovirus, migraine with 109–11
NOTCH 3 gene mutation 63–4
nutritional supplements
migraine 151, 150–2
preventive 130
obesity
chronic migraine 167
gastric bypass surgery 100, 101
obstructive sleep apnea 47
worst headache ever 86, 87
obstructive sleep apnea 48, 47–8
chronic migraine 167
occipital nerve block 159
cluster headache 156
ocular adverse events,
medication-induced 135–6
off-label prescribing 183–5
older people see elderly people
onabotulinumtoxinA 139–41, 159
muscle injection 140, 141
ondansetron, during pregnancy 114
opioids
addiction 121
chronic use 77–8
herpes zoster treatment 95
medication agreements 173
misuse 169–70
post-ictal headache 44
post-traumatic head pain 76–8
request for use 169–70
urine tests 76–8
oral contraceptive pill
estrogen-containing 5, 6
topiramate interaction 137
oxycodone 169–70
oxycodone/acetaminophen 167
oxygen therapy, cluster headache 113,
113, 155–6, 157
paranasal sinuses, innervation 41
parasthesias, with chronic migraine
131–2
patent foramen ovale (PFO)
shunt closure 158
testing in migraine with aura 157–8
patient recall 162–3
physical therapy 153
physician–patient therapeutic
relationship 165
pituitary adenoma, growth
hormone-secreting 48–9
190
policy-making, recording of medical
visits 180
polysomnogram, obstructive sleep
apnea 47–8
post-dural puncture headache 64–6
postherpetic neuralgia 96
post-ictal headache 43
incidence 45
treatment 44
postpartum headache 26–7
case 50
causes 26
cerebral venous thrombosis 50–2
diagnostic workup 27
differential diagnosis 26–7, 51
imaging 51, 51
incidence 27
primary disorder 27
post-traumatic headache (PTH) 141–3
disability determination 177–8
opioid treatment 76–8
post-viral syndrome 91
potassium supplementation,
topiramate-induced
parasthesias 131–2
preconception planning, episodic
migraine 128–30
predictive value of tests,
positive/negative 82
pregnancy
cluster headaches 155–7
discontinuing medication
preconception 130
headache management 114, 114,
115
migraine 114–15
planning on preventive treatment
129, 128–30
risk on topiramate 137
premature closure in history taking
94
preventive treatment 119–43
after head trauma 141–3
behavioral therapies 129–30
Botox use 139–41
chronic migraine with parasthesias
131–2
combination therapy 126, 126, 127,
138–9
comorbid conditions 123, 124
episodic migraine 119–21, 122
fall with migraine treatment 133–5
fatigue with drug-induced
hypotension 138–9
herbal supplements 130
medication overuse headache with
chronic migraine 132–3
multiple medical conditions 127–8
nutritional supplements 130
older woman with blurry vision on
amitriptyline 135–6
overuse of abortive treatments
132–3
pregnancy planning 129, 128–9,
130
refractory chronic migraine 124–7
seizure threshold lowering 138
seizure with tension-type headache
treatment 137–8
selection for new use 121–4
side effects 123–4
therapeutic trials 124–6
time to response 125
topiramate
contraception effects 137
long-term safety 136–7
when to consider 119
primary headache, mistaking for
another condition 20–36
prochlorperazine 108, 111
propranolol
during breast-feeding 116
headache after head injury 142
verapamil combination 138–9
proptosis, intermittent red eye with
headache 45
psychiatric illness with intractable
headache 88–90
recording of medical visits 179–80
red eye, intermittent with headache
45–6
rescue therapies 110
retinal detachment 85
reversible vasoconstrictive syndrome
(RVCS) 59–61
rhinosinusitis
acute 21–2
chronic 21, 21, 22
clinical characteristics 22
diagnosis 21
imaging 21
migraine coexistence 23
migraine differential diagnosis 22–3
nasal cavity disorders 22
recurring 21, 22
riboflavin 150–2
safety of patient, evaluation after
disclosure 89
scotoma, scintillating 5, 6, 33
seizures
with headache 43
headache relationship 43–4
medication combination 137–8
preventive treatments 138
tension-type headache treatment
137–8

self-care 169
self-diagnosis 165
serotonergic drugs, triptan interactions
104–5
serotonin syndrome 105, 104–5
sertraline, triptan interactions
104–5
severe sudden headache 59–61
sexual abuse
in childhood and psychiatric illness
with intractable headache
88–90
doctor’s response to disclosure
89–90
history taking 88–9
side-locked headache 48–9
differential diagnosis 93
imaging 93
sinus disease, diagnosis 21
sinus headache 20–3
types 21–2
sinusitis, acute sphenoid 41, 40–1
sleep hygiene 148
snoring, obstructive sleep apnea
47
Social Security Disability Insurance
(SSDI) 175, 176, 176
sphenoid sinus 41
spinal fluid pleocytosis 90–2
spinal manipulation 149, 154
risks 154–5
stabbing headache 13–15
clinical characteristics 14
differential diagnosis 13–14
incidence 14
treatment 14
stable headache, imaging 55–7
status migrainosus 111–12
steroid therapy
bridging 181
burst and taper 133
complications 181
dependence 181–2
giant cell arteritis and persistent
headache in elderly woman
92–3
hip osteonecrosis 180–1
overreliance in cluster headache
180–2
status migrainosus 111–12
treatment role in cluster headache
181
stroke
migrainous infarction 49–50
risk in migraine with aura 6
sulfa allergy with migraine 105–6
sulfonamide group 106, 106
sumatriptan
during breast-feeding 116
chest pressure from 102–4
cluster headache treatment
155–6
frequent use 119
headache after head injury 142
hemiplegic migraine treatment
96
hypersensitivity reactions 106
limited access to 112–13
postpartum headache 50–1
during pregnancy 114
SUNA (Short-lasting Unilateral
Neuralgiform attacks with
Autonomic features) 13, 14
SUNCT (Short-lasting, Unilateral,
Neuralgiform headache attacks
with Conjunctival injection
and Tearing) 13, 14
syncope
metoprolol off-label prescribing
183
orthostatic 133–5
temporal artery biopsy, giant cell
arteritis 39, 40
temporal release procedure 159
temporomandibular abnormalities
25–6
temporomandibular joint (TMJ) 25
tension-type headache
chiropractic care 153–5
diagnosis 2–4
diagnostic accuracy 3–4
history taking 1–2
migraine differential diagnosis 4,
1–4, 5
nonpharmacologic treatment
148–50
recording of medical visits 179–80
triggers 3
tetrahydrocannabinol (THC), urine
tests 77
therapeutic relationship,
physician–patient 165
thunderclap headache
acute sphenoid sinusitis 41
causes 59
imaging 59–61
reversible vasoconstrictive
syndrome 59–61
treatment 60
ticks see Lyme disease
topiramate 129
headache after head injury
142
intraocular pressure 135
long-term safety 136–7
parasthesia induction 131–2
side effects 136–7
Index
trauma
doctor’s response to disclosure
89–90
experiences 88
headache prevention after head
injury 141–3
history taking 88–9
see also post-traumatic headache
(PTH)
traumatic brain injury (TBI) 141–3
treatment imperative 168
trigeminal autonomic cephalalgias
(TACs) 12–13
hemicrania continua 17–18
trigeminal neuralgia, stabbing
headache differential diagnosis
14
trigeminocervical complex 153
triptan sensations 102–3, 104
avoidance of triptans 103
triptans
in acute headache 102
avoidance in triptan sensations
103
characteristics 103
chest pressure from sumatriptan
102–4
cluster headache treatment 9
combination therapy 102
hemiplegic migraine treatment 96
hypersensitivity reactions 106
indications for use 103–4
migraine failure to respond 100–2
migraine treatment 9, 29
post-ictal headache 44
postpartum headache 50–1
serotonergic drug interactions
104–5
side effects 104
in sulfa allergy 105–6
turbinate disorder 22
unilateral headache 7–8, 17–18
migraine 7–8, 17
urine tests
meprobamate 76–7
opioids 76–8
pitfalls 76–8
tetrahydrocannabinol 77
valproate, during breast-feeding
116
verapamil
cluster headache 181
monitoring 75–6
electrocardiographic abnormalities
75
propranolol combination
138–9
191
 Index
vertebral artery dissection (VAD)
154–5
vertigo
chronic 36
with migraine 34–6
diagnostic criteria 36
vision, normal 11
visual accompaniments, late-life
migraine 32–3
visual aura 5, 7
clinical characteristics 86
differential diagnosis 85,
85
repeated attacks 34
192
Visual Aura Rating Scale (VARS) 5, 86,
85–6
visual changes with sore head
84–6
differential diagnosis 85
tests 85–6
visual loss, giant cell arteritis 39
visual perceptual alterations with
headache 10–11
vitamin supplements, migraine 151,
150–2
vomiting
with intractable headache 109–11
status migrainosus 111
weakness and headache
diagnostic possibilities
96–7
history taking 96–8
weekend headache 41–3
weight gain in migraine 123–4
white matter lesions, familial
occurrence 62–4
differential diagnosis 62–3
imaging 62, 63
white matter lesions, incidental in
migraineur 61–2
zoster vaccine 96